Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:16][O:17][C:18]1[N:23]=[CH:22][C:21]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=2)(=[O:27])=[O:26])=[CH:20][CH:19]=1>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:24]([C:21]1[CH:22]=[N:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)[S:25]([C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=1)(=[O:26])=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCNCc1ccccc1
Reactant: O=C(Br)CBr
Reactant: COc1ccc(NS(=O)(=O)c2ccc3ccccc3c2)cn1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc2ccccc2c1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and naphthalene-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]=[O:9].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>O>[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]=[O:9]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=Cc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1C=O
Reaction time: 1.5 h
Yield: 72.3 %

Procedure:
An oily suspension of 20.8 g sodium hydride in mineral oil (50%, 0.52 mol) was washed mineral oil free by stirring with hexane 3-times and suspended in 400 ml DMF. Under stirring at ambient temperature 50.0 g (0.520 mol) imidazole-2-carbaldehyde was added to the suspension. After 1.5 h, 101.0 ml (0.572 mol) 2-(trimethylsilanyl)ethoxymethyl chloride was added and the reaction was stirred a further hour. Then excess water was added to the suspension and the reaction mixture was extracted three times with ethyl acetate. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The raw material was then purified by column chromatography (DCM) to yield 85.0 g (0.376 mol) of the SEM-protected imidazole-2-carbaldehyde.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.O>C1C=CC=CC=1>[CH:1](=[C:12]1[CH:13]=[C:8]([CH2:7][NH2:6])[CH:9]=[CH:10][NH:11]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: NCc1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)C=C1C=C(CN)C=CN1
Yield: 91.7 %

Procedure:
227 g (3.15 mols) of isobutyraldehyde is added dropwise, within 1.5 hours, to a solution of 324 g (3.0 mols) of 4-aminomethylpyridine in 300 ml of benzene, the addition being made in a manner ensuring that the temperature in the solution does not exceed 35° C. The water which has formed (about 39 g) is separated, and the benzene (with residual water) is distilled off under a slight water-jet vacuum. The residue is distilled in an oil-pump vacuum. After a small preliminary fraction of 5 g, there is obtained 445 g (2.75 mols) of isobutylidene-4-aminomethylpyridine as a slightly yellowish main fraction, corresponding to a yield of 91.5% of theory; b.p. 81.5°-82° C./133 Pa; nD20 =1.5105.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[Cl:7][CH2:8][CH2:9][NH2:10].[Cl:11][CH2:12][CH2:13]N.C(N(CC)CC)C>ClCCl.O1CCCC1>[Cl:7][CH2:8][CH2:9][N:10]([CH2:13][CH2:12][Cl:11])[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)N(CCCl)CCCl
Reaction time: 0.25 h
Yield: 82.7 %

Procedure:
14.3 ml (185 mmol) of methanesulfonyl chloride are added slowly to a solution of 15 g (84 mmol) of commercial bis(2-chloroethylamine) hydrochloride and 26 ml (185 mmol) of triethylamine in 200 ml of dichloromethane and 70 ml of tetrahydrofuran previously stirred for 15 min and then filtered in order to remove the triethylammonium chloride. The reaction medium is then stirred at ambient temperature for 18 h, extracted with dichloromethane, and washed with water. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is washed with diisopropyl ether, filtered and then dried under vacuum. 15.3 g (82%) of N,N-bis-(2-chloroethyl)methanesulfonamide are obtained in the form of a solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][C:21]#[N:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]=1)#[N:24]>C1COCC1>[C:23]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH:26]1[CH:20]([C:21]#[N:22])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:24]
Reactant: N#CC1=CCCc2ccccc21
Reactant: N#CCCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CC(Cc1ccccc1)C1CCc2ccccc2C1C#N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
To a solution of 3.5 mL (25 mmol) of diisopropylamine in 40 mL of THF at -78° C., under a nitrogen atmosphere, was added n-butyllithium (9.5 mL of a 2.5M solution in THF, 23.7 mmol) and the resultant solution was stirred at -78° C. for 0.5 h. To the stirred solution was slowly added a solution of 2.75 g (21 mmol) of 3-phenylpropiononitrile in 40 mL of THF. The reaction mixture was stirred for 45 min at -78° C. and then a solution of 3.1 g (20 mmol) of 1-cyano-3,4-dihydronaphthalene (the product of Step 1 of Example 9) in 40 mL of THF was added. The reaction mixture was stirred at -78° C. for 0.5 h and then the reaction was quenched by pouring the reaction mixture into saturated aqueous ammonium chloride solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5.70 g (quantitative yield) of the title compound as a mixture of three diastereomers; MS DCl--NH3M/Z: 287 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16](O)=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:22][CH2:23][CH2:24][C:4]2=[N:3]1.C(Cl)(=O)C(Cl)=O.C[CH2:33][N:34](CC)[CH2:35]C.CNC.Cl>C(Cl)Cl.CN(C=O)C.C1COCC1>[O:1]=[S:2]1(=[O:25])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16]([N:34]([CH3:35])[CH3:33])=[O:17])[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:22][CH2:23][CH2:24][C:4]2=[N:3]1
Reactant: O=C(O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 0.5 h

Procedure:
To a suspension of the product obtained in Step C (1.40 g, 3.91 mmol) in 20 ml of CH2Cl2 there are added 2 drops of DMF and then, dropwise, 684 μl (7.81 mmol) of oxalyl chloride diluted with 2 ml of CH2Cl2. Stirring is carried out at ambient temperature for 2 hours 30 minutes; evaporation to dryness is carried out; the residue is taken up in 15 ml of CH2Cl2; 1.1 ml (7.81 mmol) of Et3N and then 2.94 ml (5.87 mmol) of a 2M solution of dimethylamine in THF are added. Stirring is carried out at ambient temperature for 1 hour. The reaction mixture is acidified with 0.5N HCl and extracted (CH2Cl2). The organic phases are combined, washed (saturated NaCl), dried (MgSO4) and evaporated. The residue is triturated in Et2O; the title product precipitates out and is recovered by filtration. Elemental micro-analysis:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[S:29][C:11]3[N:12]([CH3:28])[C:13](=[O:27])[N:14]([CH2:17][CH2:18][CH2:19]OC4CCCCO4)[C:15](=[O:16])[C:10]=3[C:9]=2[CH:30]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl.O>[F:49][C:48]([F:51])([F:50])[C:46]([O:52][CH2:19][CH2:18][CH2:17][N:14]1[C:15](=[O:16])[C:10]2[C:9]([CH2:30][C:32]3[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=3)=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[S:29][C:11]=2[N:12]([CH3:28])[C:13]1=[O:27])=[O:47]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1c(=O)n(CCCOC(=O)C(F)(F)F)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)sc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 6-(3-chlorophenyl)-5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetra hydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 4, Step 2, 50 mg, 0.078 mmol) in TFA (1 mL) was added triethylsilane (0.5 mL). The reaction was stirred at RT for 2 h then diluted with DCM (5 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to give 3-(5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-methyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propyl 2,2,2-trifluoroacetate (40 mg, 80.5% yield) as an oil. LCMS: MH+ 571 and TR=2.327 min. Used without further purification.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[C:2]1C=CC=CC=1.C(=O)([O-])[O-:28].[Na+].[Na+].ClCC(Cl)=O.O>C(Cl)Cl>[CH2:20]([N:8]1[CH2:9][CH2:10][N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])[C:2](=[O:28])[CH2:1]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1ccccc1NCCN(Cc1ccccc1)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)CCl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(Cc2ccccc2)CC1=O
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a stirred solution of 21.6 g of N,N-dibenzyl-N'-(2-methoxyphenyl)-ethylenediamine in 400 ml methylene chloride was added 12.9 g of sodium carbonate. To this mixture, a solution of 8.42 g of chloroacetylchloride in 100 ml methylene chloride was added dropwise over 30 minutes and stirred for 1 hour. Water (500 ml) was added, the organic phase separated, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue (27.9 g) in a flask was immersed in a 180° oil bath and the formed benzylchloride removed by distillation. The crude material was chromatographed on 250 g silica gel using ether for elution. The appropriate fractions were evaporated to dryness and the solid recrystallized from isopropylether to yield 11.0 g 4-benzyl-1-(2-methoxyphenyl)-2-piperazinone in the form of yellowish crystals, mp 109°-111°, pure by TLC (ether on silica gel).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:8][C:9](C)(C)[CH3:10])(=[O:7])[CH3:6].C(O[C:16]([C:18]1[CH:19]=[C:20]2[CH:26]=[CH:25][O:24][C:21]2=[CH:22][N:23]=1)=[O:17])C.C(O)(=O)C>C1(C)C=CC=CC=1.O>[O:17]=[C:16]([C:18]1[CH:19]=[C:20]2[CH:26]=[CH:25][O:24][C:21]2=[CH:22][N:23]=1)[CH2:6][C:5]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc2ccoc2cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cc2ccoc2cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
As 510 mg (7.5 mmol) of sodium ethoxide was stirred in 5 mL toluene, 1.16 g (10.0 mmol) of t-butyl acetate was added dropwise at room temperature to the solution. Then, 956 mg (5.0 mmol) of 5-ethoxycarbonylfuro[2,3-c]pyridine dissolved in 5 mL of toluene was added dropwise at room temperature to the above solution. After all the solution had been added, the reaction mixture was heated to 60° C., and a reaction was carried out for 3 hours. The reaction solution was then cooled to 5° C. and was neutralized with 450 mg (7.5 mmol) of acetic acid as the temperature was held 5-10° C., the solution was stirred for 30 minutes as the temperature was maintained, 1 mL water was then added, and the solution was returned to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 mL of methylene chloride, and the combined organic layer was dried with anhydrous magnesium sulfate and then concentrated in a rotary evaporator. The resulting solids were recrystallized from a mixed solvent of toluene-hexane mixture, giving 933 mg (80% yield) of ethyl β-oxo-5-furo[2,3-c]pyridinepropionate in a purity of 99% by HPLC.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1Cl.[C:16]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[O:39][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:23][N:24]=2)=[CH:38][CH:37]=1
Reactant: Clc1ccncc1Br
Reactant: Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Brc1cnccc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Temperature: 130 °C

Procedure:
A resealable reaction tube was charged with cesium carbonate (0.873 g, 0.268 mmol), 3-bromo4-chloropyridine hydrochloride (0.205 g, 0.894 mmol) and 4-(4-phenylphthalazin-1-ylamino)phenol (0.280 g, 0.894 mmol) and purged with nitrogen for several minutes. 1.8 mL of DMSO was added, the tube was sealed, and the reaction mixture was heated to 130° C. for 3 h. Upon cooling the mixture was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried with MgSO4 and concentrated. N-(4-(3-bromopyridin4-yloxy)phenyl)-4-phenylphthalazin-1-amine was isolated as an orange solid. MS m/z=470 [M+H]+. Calc'd for C25H17BrN4O: 469.33.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5](Cl)[C:6]=1[C:7]#[N:8].[C:12]1([SH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C[O-].[Na+]>CO>[NH2:1][C:2]1[S:3][C:4]([CH:10]=[O:11])=[C:5]([S:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]=1[C:7]#[N:8]
Reactant: N#Cc1c(N)sc(C=O)c1Cl
Reactant: Sc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(N)sc(C=O)c1Sc1ccccc1
Yield: 81 %

Procedure:
18.7 parts of 2-amino-4-chloro-3-cyano-5-formylthiophene are added to a solution of 11 parts of thiophenol, 5.4 parts of a 30% strength methanolic sodium methylate solution and 100 parts of methanol. The mixture is heated at the boil for 0.5 hour, after which it is allowed to cool and the precipitated product is filtered off under suction, washed with methanol, and then with water and dried. 21 parts (81% of theory) of 2-amino-3-cyano-5-formyl-4-phenylthiothiophene are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:24])(=[O:23])[CH2:14][CH2:13]1)[NH:6][C:5]2=O.[NH2:26][C@H:27]1[C@H:31]([F:32])[CH2:30][N:29](C(OCC2C=CC=CC=2)=O)[CH2:28]1>>[F:32][C@@H:31]1[CH2:30][NH:29][CH2:28][C@H:27]1[NH:26][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[C:7]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[S:15](=[O:23])(=[O:24])[CH2:14][CH2:13]2)[N:6]=1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1F
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)[nH]c(=O)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(N[C@@H]3CNC[C@H]3F)c2c1

Procedure:
The title compound was prepared in analogy to Example 92-1 in Scheme 44 by using 6-methyl-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one (prepared in analogy to 6-methyl-2-(1-oxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)quinazolin-4(3H)-one in Example 91) and benzyl trans-3-amino-4-fluoropyrrolidine-1-carboxylate. MS obsd. (ESI+) [(M+H)+] 442, 1H NMR (400 MHz, CDCl3) δ ppm 8.40-8.02 (d, J=7.6 Hz, 1 H), 7.83-7.81 (d, J=7.2 Hz, 1 H), 7.52-7.49 (m, 1 H), 7.37-7.35 (d, J=10.8 Hz, 3 H), 7.22 (s, 1 H), 5.41 (s, 1 H), 5.30-5.00 (brs, 2 H), 4.90-4.55 (brs, 2 H), 3.70-3.68 (d, J=5.2 Hz, 1 H), 3.48 (s, 2 H), 3.31-3.25 (brs, 2 H) 2.95 (s, 1 H), 2.38 (s, 3 H), 2.20-2.18 (d, J=8.8 Hz, 1 H).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18]>CN(C=O)C>[CH2:16]=[C:17]1[CH2:19][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:18]1
Reactant: C=C(CCl)CCl
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2OC1

Procedure:
A solution of catechol (4.4 g, 40 mmol), Cs2CO3 (27.7 g, 85 mmol) and 3-chloro-2 chloromethyl-prop-1-ene(5 g, 40 mmol) in DMF (80 mL) was striired overnight at rt. The reaction was partitioned between ether and water and the organic extract was washed with brine, dried (MgSO4), filtered and concentrated to 5.46 g (84%) of a yellow oil. MS 163 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][C:11](O)([CH3:13])C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC(O)[CH2:26][O:27]CC)C1C=CC=CC=1)C.C(N(CC(O)COC)C1C=CC=CC=1)C>>[CH2:1]([N:3]([CH2:10][CH2:11][CH2:13][CH2:26][OH:27])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOCC(O)CN(CC)c1ccccc1
Reactant: CCN(CC(C)(C)O)c1ccccc1
Agent: CCN(CC(O)COC)c1ccccc1
Product: CCN(CCCCO)c1ccccc1

Procedure:
N-ethyl-N-(2-hydroxyisobutyl)aniline 3N-ethyl-N-(2-hydroxy-3-methoxypropyl)aniline N-ethyl-N-(2-hydroxy-3 -ethoxypropyl)aniline
Reaction SMILES: C([O:3][C:4](=[O:23])/[CH:5]=[C:6](\[CH3:22])/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[C:16](C)[O:15][C:14]=1[CH3:20])C.[OH-].[K+:25].O>CO>[CH3:22]/[C:6](/[CH:7]=[CH:8]/[CH:9]=[C:10](\[CH3:21])/[CH:11]=[CH:12]/[C:13]1[C:17]([CH3:18])=[CH:16][O:15][C:14]=1[CH3:20])=[CH:5]\[C:4]([O-:23])=[O:3].[K+:25]
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)oc(C)c1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(/C=C/c1c(C)coc1C)=C\C=C\C(C)=C\C(=O)[O-]

Procedure:
(E,E,E,E)-3,7-dimethyl-9-(2,4,5-trimethyl-3-furyl)-2,4,6,8-nonatetraenoic acid ethyl ester (16 g.) was dissolved in methanol (100 ml.) containing potassium hydroxide (10 g.) and water (20 ml.) and the resulting mixture was heated at reflux for 1 hour. On cooling, a potassium salt crystallized out. This was filtered off, washed with methanol and crystallized from isopropanol-water to give pure potassium (E,E,E,E)-3,7-dimethyl-9-(2,4-dimethyl-3-furyl)-2,4,6,8-nonatetraenoate, m.p. 265°-70° (dec.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([Cl:24])=[O:23]>C(Cl)(Cl)Cl>[ClH:24].[O:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)=[O:23]
Reactant: O=C(Cl)c1ccco1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: ClC(Cl)Cl
Product: CN1CCC(c2nn(C(=O)c3ccco3)c3ccccc23)CC1
Product: Cl
Yield: 51.5 %

Procedure:
A mixture of 4.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole, 2.7 ml of 2-furoyl chloride (95% pure) and 60 ml of chloroform was refluxed for 3 hrs. The mixture was filtered. The filtrate was evaporated under reduced pressure, the residue was triturated and ethyl acetate and the solid was collected. The solid and filtrate were combined and recrystallized twice from ethanol to yield 3.3 g (51.5%) of product, mp 268°-270° C.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=O)C.Cl.[CH3:16]O>>[NH2:4][C:5]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:16])=[O:8]
Reactant: CO
Reactant: CC(=O)Nc1cc(I)ccc1C(=O)O
Agent: Cl
Product: COC(=O)c1ccc(I)cc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 16.1 g of 2-acetylamino-4-iodobenzoic acid (m.p. 233°-5° C.; synthesized in accordance with U.S. Pat. No. 4,762,838) in 325 ml of absolute methanol is saturated at 0° C. with dry hydrogen chloride gas. The mixture is heated to the boil for 15 hours, cooled to room temperature, resaturated using dry hydrogen chloride gas, and allowed to stand at room temperature for 24 hours. The solvent is evaporated in vacuo, the residue is taken up in dichloromethane, and the organic phase is washed with a saturated aqueous sodium hydrogen carbonate solution until free from acid. The organic phase is dried over Na2SO4, and evaporated in vacuo. This gives 13.8 g of methyl 2-amino-4-iodobenzoate of m.p. 63°-7° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(#N)C.ClCCl>[CH:24]([NH:27][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(Cl)nncc3c2)c1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C)c(-c2ccc3c(NC(C)C)nncc3c2)c1
Temperature: 140 °C

Procedure:
Ethyl 3-(1-chlorophthalazin-6-yl)-4-methylbenzoate (1.4 g) in acetonitrile (10 mL) was treated with isopropylamine (8 mL, 89 mmol). The mixture was stirred at 140° C. (sealed tube) for 15 h. The mixture was dissolved in 100 mL dichloromethane and was washed with water (20 mL), brine (20 mL), then dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 50% ethyl acetate/DCM to give ethyl 3-(1-(isopropylamino)phthalazin-6-yl)-4-methylbenzoate as a white solid.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([N:19]2[C:23]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[N:22][N:21]=[C:20]2C(OCC)=O)=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([O:15][CH3:16])[C:8]([O:17][CH3:18])=[N:7]2.C(O)(=O)C>O1CCOCC1.O>[Cl:3][C:4]1[C:5]([N:19]2[CH:20]=[N:21][N:22]=[C:23]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[C:6]2[C:11](=[CH:12][C:13]=1[Cl:14])[N:10]=[C:9]([O:15][CH3:16])[C:8]([O:17][CH3:18])=[N:7]2
Reactant: CCOC(=O)c1nnc(-c2cccnc2)n1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: COc1nc2cc(Cl)c(Cl)c(-n3cnnc3-c3cccnc3)c2nc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.7 %

Procedure:
1M Aqueous sodium hydroxide solution (17.25 mL, 17.25 mmol) was added dropwise to a stirred solution of 6,7-dichloro-2,3-dimethoxy-5-[3-ethoxycarbonyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl]quinoxaline (Preparation 94, 8.2 g, 17.25 mmol) in 1,4-dioxane (68 mL) and water (50 mL) at 10° C. The solution was warmed to room temperature and stirred for 20 hours, diluted with water (50 mL), acidified with glacial acetic acid and extracted with ethyl acetate (1×100 mL, 2×50 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using dichloromethane:methanol (1:0 changing to 9:1, by volume) to give the title compound (5.82 g, 84%) as a white solid, mp 206-207° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[H-].[Na+].I[CH3:16]>O1CCCC1>[CH3:16][O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.3 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (J. Med. Chem. 2001, 44, 94., 130 mg, 0.75 mmol) in tetrahydrofuran (1.5 mL) was added sodium hydride (60% in mineral oil dispersion, 36 mg, 0.90 mmol) slowly at 0° C. After 30 min., iodomethane (130 mg, 0.90 mmol) was added to the mixture at 0° C. The mixture was gradually warmed to room temperature and stirred overnight. The mixture was concentrated and purified by column chromatography on silica gel eluting with hexane/ethyl acetate (6/1) to afford 110 mg (76%) of the title compound as a colorless oil: