Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[BH4-].[Na+]>CO>[OH:1][CH:2]([CH2:3][C:4]([O:6][CH3:7])=[O:5])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(O)CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (20 g, 115 mmol) in anhydrous MeOH (140 mL) was added NaBH4 (2.33 g, 63.18 mmol) in small portions over 10 minutes. The mixture was stirred for 1 h at room temperature and concentrated. Water and EtOAc was added and the organic phase was separated and dried. The combined organic layer was concentrated to give the crude product, which was purified by column chromatography to give dimethyl 3-hydroxypentanedioate (9 g, 44%). 1H-NMR (CDCl3): 2.51 (m, 4H), 3.43 (m, 1H), 3.70 (m, 6H), 4.45 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[C:11]([N:14]1[C:18](=[O:19])[CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)S[CH2:15]1)([CH3:13])[CH3:12].ClC1C=CC=C(C(OO)=O)C=1.[S:38]([O-:42])([O-])(=[O:40])=S.[Na+].[Na+]>ClCCl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:26])[C:11]([N:14]1[C:18](=[O:19])[CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:38](=[O:42])(=[O:40])[CH2:15]1)([CH3:12])[CH3:13]
Reactant: O=S([O-])([O-])=S
Reactant: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CSC(c2ccccc2)C1=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CS(=O)(=O)C(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2,5-difluorophenyl)-2-(5-phenylthiazolidin-4-on-3-yl)isobutyramide (1.3 g) prepared according to Example 13 in dichloromethane (25 mL) was added portionwise 70% m-chloroperbenzoic acid (1 g) under ice-cooling, and the mixture was stirred for 30 minutes at room temperature. After adding a small amount of sodium thiosulfate, the mixture was diluted with chloroform and washed with a saturated sodium hydrogencarbonate aqueous solution. After distilling off the solvent under reduced pressure, the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: chloroform/ethyl acetate=3/1) to give crystals, which were washed with a mixture of isopropyl ether-ethanol (10:1) to give 0.26 g of the title compound as crystals.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)Cl>[C:28]([N:8]1[CH2:14][CH2:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:11][CH2:10][CH2:9]1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cl
Reactant: c1ccc(CN2CCOC(c3ccccc3)(c3ccccc3)CC2)cc1
Solvent: ClCCl
Product: CCOC(=O)N1CCOC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 30.25 g of 4-benzyl-7,7-diphenyl-hexahydro-1,4-oxazepine in 300 ml of methylene chloride, that of 10.4 g of ethyl chloroformate in 100 ml of methylene chloride is added dropwise while stirring. After 30 minutes the mixture is allowed to warm up to room temperature and stirred for 15 hours. It is successively washed twice with 50 ml of N hydrochloric acid, 50 ml of N aqueous sodium hydroxide and 50 ml of saturated sodium chloride each, dried, filtered and evaporated. The residue is recrystallized from hexane, to yield the 4-carbethoxy-7,7-diphenyl-hexahydro-1,4-oxazepine melting at 122° to 123°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[I:12]I>CO.O>[OH:1][C:2]1[C:3]([I:12])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Oc1ccc2ncccc2c1
Reactant: II
Solvent: O
Solvent: CO
Product: Oc1ccc2ncccc2c1I
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.9 %

Procedure:
6-Hydroxyquinoline (0.5 g) and iodine (1.24 g) were dissolved in methanol/water (15 ml/7.5 ml) to prepare a solution which was then stirred at room temperature for 2 hr. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was washed with ethyl acetate to give 6-hydroxy-5-iodo-quinoline (419 mg, yield 45%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:20]1[C@H:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:24](=[O:30])[NH:23][C@H:22]([CH:31]2[CH2:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32]2)[C:21]1=[O:40])[C:10](NC1C=CC=CC=1O)=[O:11].C(N1C=CN=C1)(N1C=CN=C1)=[O:42]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([N:20]1[C@H:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:24](=[O:30])[NH:23][C@H:22]([CH:31]2[CH2:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:39]2)[C:21]1=[O:40])[C:10]([OH:42])=[O:11]
Reactant: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(F)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)C[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)O)c1ccc(F)cc1F
Reaction time: 16 h
Yield: 69 %

Procedure:
(2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-(2-hydroxyphenyl)ethanamide (2.650 g) was stirred in dichloromethane (20 ml) and carbonyldiimidazole (1.178 g) was added. the mixture was left at room temperature for 16 hours then the solvent was removed under reduced pressure. The residue was then taken up in 1:1 acetone:water (v/v) (80 ml) and left at room temperature for 30 minutes. The bulk of the acetone was then removed under reduced pressure and the residue was partitioned between dichloromethane and 0.5M hydrochloric acid. The organic phase was separated (hydrophobic frit) and evaporated under reduced pressure. The crude product was purified (Biotage™ flash chromatography column, 90 g silica cartridge eluted with (i) 1:1 ethyl acetate:cyclohexane (ii) ethyl acetate (iii) ethyl acetate:methanol 9:1) to afford (2RS)-2-(2,4-difluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-ethanoic acid as a colourless solid 1.524 g as a mixture of epimers.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([CH3:25])[C:12]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=1)([OH:17])[C:13]([F:16])([F:15])[F:14])[C:5](O)=[O:6].[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([CH:11]([CH3:25])[C:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=3)([OH:17])[C:13]([F:16])([F:14])[F:15])=[C:2]([Cl:1])[CH:3]=2)[CH:30]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: CC(c1ccc(C(=O)O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cccc(NC(=O)c2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)c1

Procedure:
In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid, Example 26, step 3, was reacted with methyl-3-aminobenzoate and HBTU at 80° C. 4 h to give the title compound as a white solid. MS (m/e)=527.3 [M+H+].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:16][CH2:15]1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(OCCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 4-fluoro-2-(methyloxy)-1-nitrobenzene (1 g, 5.8 mmol) in 20 mL of anhydrous DMF was added 2-(4-methyl-1-piperazinyl)ethanol (1.09 g, 7.6 mmol). Sodium hydride (60%) (467 mg, 11.68 mmol) was added portionwise. The reaction was stirred at rt for 30 min at which time the reaction was diluted with ethyl acetate and washed with water and a saturated sodium chloride solution. Solvents were removed under reduced pressure to give 1.7 g of crude 1-methyl-4-(2-{[3-(methyloxy)-4-nitrophenyl]oxy}ethyl)piperazine as a yellow solid. ESIMS (M+H)+=296.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[OH2:21].CCCCCC>C(O)(=O)C>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[O:21])[C:5]=2[CH:4]=[CH:3][C:2]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18]
Reactant: O
Reactant: CC(C(=O)O)c1ccc2c(c1)C=Cc1ccccc1C2
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Yield: 30 %

Procedure:
1.10 Gm. of 2-(5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid is refluxed for 2 hours in 10 ml. of acetic acid and 7.5 ml. of water containing 2.24 gm. of ceric ammonium nitrate. The solution is poured into water and extracted with ethyl acetate. The extract is washed, dried and evaporated and the residue chromatographed on silica gel, eluting with 40:60:1 ethyl acetate:hexane:acetic acid, so as to isolate a 30% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8]OS1(=O)=O.[S:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[Li]>>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][CH2:9][CH2:8][C:17]1[S:16][CH:20]=[CH:19][CH:18]=1
Reactant: O=S1(=O)OCCN1Cc1ccccc1Cl
Reactant: [Li]c1cccs1
Product: Clc1ccccc1CNCCc1cccs1

Procedure:
contacting the N-(2-chlorobenzyl)-2,2-dioxo-1,2,3-oxathiazolidine with thienyllithium to give N-(2-chlorobenzyl)-2-(2-thienyl)ethylamine, and
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15](N3C=NC=N3)[C:16]=2[N:17]=1.[F:24][CH2:25][CH2:26][OH:27]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]=[C:13]([NH2:23])[N:14]=[C:15]([O:27][CH2:26][CH2:25][F:24])[C:16]=2[N:17]=1
Reactant: OCCF
Reactant: Nc1nc(-n2cncn2)c2nc(Cl)ccc2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Product: Nc1nc(OCCF)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
Potassium tert-butoxide (2.8 mL; 1M in THF) was added to a suspension of 6-chloro-4-[1,2,4]triazol-1-yl-pyrido[3,2-d]pyrimidin-2-ylamine (0.7 g) and 2-fluoroethanol (0.83 mL) in DCM (100 mL). After stirring at room temperature for 10 minutes, the mixture was diluted with DCM (100 mL) and washed with brine. The organic layer was dried over Na2SO4 and concentrated to afford 6-chloro-4-(2-fluoro-ethoxy)-pyrido[3,2-d]pyrimidin-2-ylamine as a yellow solid (0.3 g, yield: 44%) was characterized by its mass spectrum as follows: MS (m/z) 243.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14]C)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Br:23]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:23])[N:6]2[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrBr
Reactant: COCCOc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(OCCO)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
6-Amino-9-benzyl-2-(2-methoxyethoxy)purine (100 mg, 0.36 mmol) and bromine (0.25 ml) were dissolved in methylene chloride (100 ml). The solution was stirred at room temperature for 6 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (2% methanol/chloroform) to give the subject compound (55 mg, yield 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:19][CH3:20])=[O:17])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[O:29][CH3:30].C(O)(C(F)(F)F)=O>ClCCl>[NH2:21][C@@H:18]([CH2:19][CH3:20])[C:16]([NH:15][C:12]1[CH:13]=[N:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([O:29][CH3:30])[CH:4]=2)=[CH:10][CH:11]=1)=[O:17]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](N)C(=O)Nc1ccc(Oc2ccc(C)c(OC)c2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
To a solution of 1,1-dimethylethyl ((1S)-1-{[(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 66, 70 mg) in dichloromethane (2.5 mL) cooled down to 0° C. TFA (0.779 mL, 10.11 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 hours and then evaporated. The residue was diluted with dichloromethane (10 mL) and neutralized with a saturated aqueous solution of NaHCO3 (15 mL). The organic phase was separated, dried over sodium sulphate, filtered and evaporated to afford the title compound as a yellow pale oil (53.1 mg).
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=O)[CH3:14]>CCO.O>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3](=[O:12])[CH:14]=[CH:13][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccccc1
Reactant: COc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 56 %

Procedure:
Step A Add 10% aqueous NaOH (38 mL) to a solution of p-anisaldehyde (25 mL, 0.206 mol) and acetophenone (23.97 mL, 0.206 mol) in EtOH (500 mL). Stir the mixture at room temperature over night. Dilute the mixture with water and extract with ether. Combine the ethereal extracts, wash with water and brine, dry over Na2SO4 and concentrate to a solid. Recrystallize the solid from ether/hexanes to provide 27.51 g (56%) of 4'-methoxychalcone, mp 72°-74° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[C:27]1([CH:33]([CH3:36])[CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([CH3:36])[CH2:34][NH:35][S:12]([N:9]2[CH2:10][CH2:11][C:6]3([C:2](=[O:1])[N:3]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)(=[O:14])=[O:13])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CC(CN)c1ccccc1
Product: CC(CNS(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1)c1ccccc1

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and 2-phenyl-propylamine. MS (ESI): 512.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH3:16])[C:8]=3[CH2:17]2)=[C:4]([C:19](OC)=[O:20])[C:3]=1[C:23](OC)=[O:24].[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[CH3:1][C:2]1[N:18]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH3:16])[C:8]=3[CH2:17]2)=[C:4]([CH2:19][OH:20])[C:3]=1[CH2:23][OH:24]
Reactant: COC(=O)c1c(C(=O)OC)c2n(c1C)Cc1c(c3ccccc3n1C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1c(CO)c(CO)c2n1Cc1c(c3ccccc3n1C)C2
Reaction time: 0.25 h

Procedure:
A solution of dimethyl 3,6-dimethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-dicarboxylate (3.5 g, 10.0 mmol) in anhydrous dichloromethane (35 mL) was added dropwise into a stirred suspension of LiAlH4 (0.9 g, 25.0 mmol) in anhydrous diethyl ether (20 mL) at 0 to −5° C. The reaction mixture was further stirred for 15 min after the addition was completed. The excess hydride was destroyed by the sequential addition of water (1 mL), 15% aqueous NaOH (1 mL), and water (1 mL) at 0° C. The mixture was filtered through a pad of Celite, the solid residue was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness in vacuo. The residue was triturated with ether to give [3,6-dimethyl-6,11-dihydro-5H-indolizino[6,7-b]indole-1,2-diyl]dimethanol (BO-1922), 2.3 g (79%); mp 200-201° C. 1H NMR (DMSO-d6) δ 2.29 (3H, s, Me), 3.73 (3H, s, Me), 3.99 (2H, s, CH2), 4.38 (4H, brs, CH2 and exchangeable, OH), 4.44 (2H, s, CH2), 5.13 (2H, s, CH2), 7.05 (1H, t, J=7.4 Hz, ArH), 7.16 (1H, t, J=7.4 Hz, ArH), 7.46 (1H, d, J=7.8 Hz, ArH), 7.53 (1H, d, J=7.8 Hz, ArH). Anal. Calcd for (C18H20N2O2.0.5H2O): C, 70.80; H, 6.93; N, 9.17. Found: C, 70.85; H, 6.65; N, 9.02.
Reaction SMILES: [CH3:1][O-:2].[Na+].[N:4]1([CH:9](Cl)[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][CH3:12])[CH:8]=[N:7][CH:6]=[N:5]1.O>CO.[I-].[K+]>[N:4]1([CH:9]([O:2][CH3:1])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH2:11][CH3:12])[CH:8]=[N:7][CH:6]=[N:5]1
Reactant: CCC(c1ccc(Cl)cc1Cl)C(Cl)n1cncn1
Reactant: C[O-]
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(c1ccc(Cl)cc1Cl)C(OC)n1cncn1
Yield: 23.7 %

Procedure:
9.4 g of sodium methylate and 0.2 g of potassium iodide are added to a solution of 26.6 g of 1-(1,2,4-triazol-1-yl)-1-chloro-2-(2,4-dichlorophenyl)-butane in 200 ml of methanol. The reaction mixture is refluxed for 48 hours, after which 100 ml of water are added to the solution and the mixture is extracted several times with methyl tert-butyl ether. The organic phase isolated is washed twice with water, then dried over sodium sulfate and evaporated down and the remaining residue is purified by chromatography over silica gel (9:1 ethyl acetate/n-hexane). 6.2 g (24%) of 1-(1,2,4-triazol-1-yl)-1-methoxy-2-(2,4-dichlorophenyl)-butane are obtained as a 1:1 diastereomer mixture [compound No. 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[F:33])[CH2:23][CH2:22]1>>[F:33][C:32]1[CH:31]=[CH:30][C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])=[CH:28][C:27]=1[CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:14]([C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[O:16])[CH2:26][CH2:25]1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCCC1
Reactant: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1ccc(F)c(C2CCN(CCCNC(=O)C3(c4ccc(F)cc4)CCCCC3)CC2)c1

Procedure:
Example 131 was prepared from 1-(4-fluorophenyl)cyclohexanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-fluorophenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.43 (dd, 1H, J=6.9, 2.5 Hz), 7.36–7.31 (m, 2H), 7.23–7.17 (m, 1H), 6.93 (t, 2H, J=8.4 Hz), 6.87 (t, 1H, J=8.9 Hz), 6.73–6.68 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.73–2.65 (m, 1H), 2.45 (septet, 1H, J=6.7 Hz), 2.30–2.21 (m, 4H), 1.9–1.77 (m, 5H), 1.70–1.63 (m, 3H), 1.56–1.45 (m, 8H), 1.17 (d, 6H, J=6.7 Hz); ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9](Cl)=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1>C1(C)C=CC=CC=1>[OH:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][C:8]=1[C:9]([NH:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=[O:10]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1O
Reactant: Nc1nnn[nH]1
Solvent: Cc1ccccc1
Product: O=C(Nc1nnn[nH]1)c1cc([N+](=O)[O-])ccc1O

Procedure:
The 5-nitrosalicyloyl chloride thus obtained was dissolved in dry toluene (40 ml) and treated with anhydrous 5-aminotetrazole (3.4 g) and the mixture was stirred and heated at reflux for 12 hours. The mixture was then allowed to cool and was treated with petroleum ether (b.p. 40°-60° C.; 40 ml). The resulting solid was filtered off, washed with petroleum ether (b.p. 40°-60° C.) and stirred with hydrochloric acid (2N; 100 ml). The undissolved solid was filtered off, washed with hydrochloric acid (2N) and with water, and was then dried and dissolved in glacial acetic acid (750 ml). The solution was filtered hot and was then concentrated to 150 ml volume and was then cooled and filtered to give 2-hydroxy-5-nitro-N-(tetrazol-5-yl)-benzamide (2.2 g), m.p. 271°-272° C. (with decomposition).
Reaction SMILES: [CH:1]([N:4]([C:8]1[CH:13]=[CH:12][C:11]2[O:14][CH2:15][O:16][C:10]=2[CH:9]=1)[C:5]([NH2:7])=[O:6])([CH3:3])[CH3:2].[CH2:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=O)=[CH:23][CH:24]=2)[CH2:19][CH2:18]1>>[CH:1]([N:4]1[C:8]2[C:13](=[CH:12][C:11]3[O:14][CH2:15][O:16][C:10]=3[CH:9]=2)[CH:26]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[CH2:17][CH2:18][CH2:19]3)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(N)=O)c1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)CCC2
Product: CC(C)N1C(=O)NC(c2ccc3c(c2)CCC3)c2cc3c(cc21)OCO3
Yield: 59 %

Procedure:
This compound was synthesized from N-isopropyl-N-[3,4-(methylenedioxy)-phenyl]urea (291 mg) and 5-indancarboxaldehyde (190 mg) by the procedure described in example 10 in 59% yield, mp: 146-148° C. 1H NMR (CDCl3): 7.21-7.04 (m, 3H), 6.67 (s, 1H), 6.30 (s, 1H), 5.91 (d, J=1.4, 1H), 5.89 (d, J=1.4. 1H), 5.27 (s, 1H), 5.00 (s, 1H), 4.45 (m, 1H), 2.89 (m, 4H), 2.08 (m, 2H), 2.08 (m, 2H), 1.58-1.55 (m, 6H). Anal. calcd. for C21N22O3; C, 71.98; H, 6.33; N, 7.99. Found: C, 72.25; H, 6.59; N, 7.89.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11]S(C)=O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:11])[CH2:9][O:10]2)=[CH:4][CH:3]=1
Reactant: CS(C)=O
Reactant: CC(=O)c1ccc(F)cc1
Solvent: O
Product: CC1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(4-fluorophenyl)ethanone (1 equiv.) in DMSO is added to the reaction mixture dropwise over 20 min. and stirred at RT for 4 h. The reaction is monitored by TLC and at completion the reaction mixture is poured in water (100 mL) and extracted with EtOAc. The combined organic extract is washed with water, followed by brine, dried over sodium sulfate and evaporated to dryness.