Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:20])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:21]12[CH2:28][CH2:27][CH:24]([CH2:25][CH2:26]1)[CH:23](O)[CH2:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]([CH3:18])[C:16](=[O:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:20][CH:23]4[CH:24]5[CH2:27][CH2:28][N:21]([CH2:26][CH2:25]5)[CH2:22]4)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2cccc(Cl)c2)nc2ccc(O)cc2c1=O
Reactant: OC1CN2CCC1CC2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cn1c(-c2cccc(Cl)c2)nc2ccc(OC3CN4CCC3CC4)cc2c1=O
Reaction time: 20 h
Yield: 12.9 %

Procedure:
To a solution of 2-(3-chlorophenyl)-6-hydroxy-3-methylquinazolin-4(3H)-one (Intermediate 33A) (100 mg, 0.35 mmol), 3-quinuclidinol (44 mg, 0.35 mmol) and triphenylphosphine (137 mg, 0.35 mmol) in tetrahydrofuran (2 mL) was added dropwise diisopropyl azodicarboxylate (0.103 mL, 0.52 mmol). The reaction was stirred for 20 h. The mixture was purified by scx cartridge (1 g) followed by acidic prep hplc then scx (500 mg) to afford 2-(3-chlorophenyl)-3-methyl-6-(quinuclidin-3-yloxy)quinazolin-4(3H)-one (18 mg, 0.045 mmol).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH:5]3[NH2:12])[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:26]([NH:12][CH:5]1[CH:4]2[CH2:10][CH:8]3[CH2:9][C:2]([OH:1])([CH2:11][CH:6]1[CH2:7]3)[CH2:3]2)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC12CC3CC(C1)C(NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C3)C2
Reaction time: 0.17 h

Procedure:
5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (2.0 g; 0.012 mole) is dissolved in 70 ml of dichloromethane with gentle heating. To this is added triethylamine (2.4 g; 0.024 mole) and cooled in an ice bath. To this is added triphenylmethyl chloride (3.34 g; 0.012 mole) in dichloromethane (10 ml) all at once. The reaction is stirred for 10 minutes with ice cooling and then 5 hours at room temperature. The reaction mixture is heated to reflux overnight, cooled, filtered and evaporated to dryness. Purification is accomplished via HPLC (eluting with 20% ethyl acetate/hexane) to obtain N-trityl-5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine (m.p. 166°-170° C.) which is used directly in step E.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1C=CC(SC)=C(Cl)C=1.ICC1CC[O:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([CH:6]1[CH2:5][CH2:7][O:31][CH2:30]1)[CH3:17]
Reactant: CC(C)NC(C)C
Reactant: ICC1CCOC1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(C)C1CCOC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A solution of diisopropylamine (0.84 mL, 5.98 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. under an argon atmosphere and then was treated with a 2.5M solution of n-butyllithium in hexanes (2.29 mL, 5.72 mmol). The reaction mixture was stirred at −78° C. for 15 min. At this time, the reaction was slowly treated with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 1.20 g, 5.20 mmol) in tetrahydrofuran (5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.75 mL). The bright yellow solution was allowed to stir at −78° C. for 1 h, after which time, a solution of 3-iodomethyl-tetrahydro-furan (2.21 g, 10.4 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.69 mL) and tetrahydrofuran (5 mL) was added via a cannula. The reaction mixture was then allowed to warm to 25° C., where it was stirred for 48 h. The reaction mixture was then quenched by the addition of a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate 3×30 mL). The organic layers were then combined and washed with a 10% aqueous sulfuric acid solution (25 mL) and a saturated aqueous sodium bicarbonate solution (25 mL). The combined organic layers were then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 75/25 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(tetrahydro-furan-3-yl-propionic acid methyl ester (663 mg, 41%) as a light yellow oil: EI-HRMS m/e calcd for C15H19ClO3S (M+) 314.0743. found 314.0729.
Reaction SMILES: O=[C:2]([CH3:18])[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:18][C:2]1[O:11][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][C:3]=1[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(NC(=O)c1cccnc1)C(C)=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1nc(-c2cccnc2)oc1C
Temperature: 0 °C
Yield: 108.7 %

Procedure:
Intermediate 32 (110 mg) was treated with phosphorous oxychloride (0.51 ml) in toluene (2 ml) and the mixture heated under reflux for 3.5 h. The mixture was poured into ice cold saturated aqueous sodium bicarbonate (30 ml) and extracted with dichloromethane (20 ml). The organic layer was evaporated in vacuo to give a yellow gum (111 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)C>[C:14]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1)(=[O:16])[CH3:15]
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(NC(C)=O)cc1OC
Temperature: 62.5 °C
Yield: 88.1 %

Procedure:
To a solution of methyl 4-amino-2-methoxybenzoate (501 mg, 2.77 mmol) in ethanol (8 ml) was added acetic anhydride (0.42 ml, 4.44 mmol, 1.6 eq) and the clear solution heated at 60-65° C. for 2 h. After cooling to room temperature the solvent was removed by rotary evaporator and the residue treated with water (10 ml) and saturated sodium bicarbonate solution (10 ml) before extracting with ethyl acetate (20 ml, 2×10 ml). The combined ethyl acetate extract was washed with water, then brine, dried (MgSO4) and evaporated to give methyl 4-acetamido-2-methoxybenzoate (545 mg, 88%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][C:25](=[O:27])[CH2:24][CH2:23][CH:22]2[C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[O:10][C:9]1([CH3:36])[CH3:35])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH2:26][CH:25]([OH:27])[CH2:24][CH2:23][CH:22]2[C:28](=[O:34])[NH:29][C:30]([CH3:33])([CH3:32])[CH3:31])[O:10][C:9]1([CH3:36])[CH3:35])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)NC(=O)C1CCC(=O)CC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)C1CCC(O)CC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A solution of 4-benzyl-5-(2-tert-butylcarbamoyl-5-oxo-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (980 mg, 1.96 mmol) in dry tetrahydrofuran was stirred at −78° C. under nitrogen during the addition of 1 M L-selectride solution in tetrahydrofuran (2.5 ml, 2.5 mmol). The resulting mixture was stirred at −78° C. for 30 minutes and then quenched by the addition of saturated aqueous ammonium chloride solution and allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with 2N aqueous hydrogen chloride solution and brine, dried (anhydrous magnesium sulfate) and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexane: 7/3 to 1/0) provided of 4-benzyl-5-(2-tert-butylcarbamoyl-5-hydroxy-cyclohexylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (934 mg, 95%) as a white foam.
Reaction SMILES: [OH:1][C:2]1([CH2:12][CH:13]=O)[CH2:11][CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH2:13][CH2:12][C:2]2([OH:1])[CH2:11][CH2:10][CH2:9][C:4]3([O:5][CH2:6][CH2:7][O:8]3)[CH2:3]2)[CH3:23])=[CH:18][CH:17]=1
Reactant: C[C@H](N)c1ccc(Br)cc1
Reactant: O=CCC1(O)CCCC2(C1)OCCO2
Product: C[C@H](NCCC1(O)CCCC2(C1)OCCO2)c1ccc(Br)cc1
Yield: 68 %

Procedure:
The title compound is prepared from (7-hydroxy-1,4-dioxa-spiro[4.5]dec-7-yl)-acetaldehyde and (S)-1-(4-bromo-phenyl)-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 68% of theory; LC (method 1): tR=3.83 min; Mass spectrum (ESI+): m/z=384/386 (Br) [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[OH:20][C:21]1[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:24][CH:25]=1>O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:20][C:21]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[S:24][CH:25]=2)[N:3]=1
Reactant: Oc1csc(C(F)(F)F)c1
Reactant: Fc1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cccc(Oc2csc(C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
1.00 g of 2,6-difluoropyridine is introduced into 10 ml of DMF under nitrogen and 1.44 g of K2CO3 are added at RT. 1.61 g of 4-hydroxy-2-trifluoromethylthiophene are added and the mixture is heated at 80° C. for 4 h, then cooled to RT and poured into water. After extraction twice with heptane/ethyl acetate (1:1) and twice with ethyl acetate the product is washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel with heptane/ethyl acetate (3:7) as eluent gives 1.7 g of 2-fluoro-6-(2-trifluoromethyl-4-thienyloxy)pyridine as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[N+:38]([C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44]Cl)([O-:40])=[O:39].[H-].[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:29])[CH2:3][CH:2]2[O:1][CH2:44][C:43]2[CH:46]=[CH:47][CH:48]=[C:41]([N+:38]([O-:40])=[O:39])[CH:42]=2)=[CH:9][CH:10]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reactant: O=[N+]([O-])c1cccc(CCl)c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2)cc1
Temperature: -10 °C
Reaction time: 2.5 h

Procedure:
The solution of 0.512 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.355 g of 3-nitrobenzyl chloride in 3.0 ml of N,N-dimethylformamide is admixed with stirring at −10° C. with 0.022 g of sodium hydride dispersion (60%). The reaction mixture is stirred at −10° C. over 2.5 hours, then poured onto 1M aqueous sodium hydrogencarbonate solution (25 ml) and extracted with ethyl acetate (2×25 ml). The organic phases are washed successively with water (2×25 ml) and brine (1×25 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (1:1 EtOAc-heptane); Rt=5.94.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH2:22][O:23][CH3:24])[C:19]([C:25]1[N:29]=[CH:28][NH:27][N:26]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6].CI.[C:32](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[N:20]([CH2:22][O:23][CH3:24])[C:19]([C:25]1[N:26]([CH3:32])[N:27]=[CH:28][N:29]=1)=[CH:18]2)[S:5]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])=[O:6]
Reactant: O=C([O-])[O-]
Reactant: COCN(c1cccc2cc(-c3nc[nH]n3)n(COC)c12)S(=O)(=O)c1cccs1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COCN(c1cccc2cc(-c3ncnn3C)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A mixture of N-(methoxymethyl)-N-[1-(methoxymethyl)-2-(1H-1,2,4-triazol-3-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.70 g), methyl iodide (0.20 mL), potassium carbonate (0.25 g) and N,N-dimethylformamide (8 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.14 g, yield 19%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:4-1:0, volume ratio). melting point 110-111° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:23](=[O:32])[C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:16]=1>>[CH3:12][O:13][C:14](=[O:39])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:22]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)/[C:24](=[C:25](/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)\[C:2]3[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH2:11])=[CH:4][CH:3]=3)/[C:23]2=[O:32])[CH:16]=1
Reactant: NS(=O)(=O)c1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(S(N)(=O)=O)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 4-iodo-benzenesulfonamide (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.90 (s, 3H), 4.95 (s, 2H), 5.02 (s, 2H), 6.41 (d, 1H), 6.65-6.71 (m, 2H), 7.09 (t, 1H), 7.26-7.33 (m, 2H), 7.35-7.42 (m, 6H), 7.58-7.60 (m, 3H), 7.99 (d, 1H), 8.07 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=O)[C:5]2=[O:14].[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[C:6]([CH:12]=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]2=[O:14]
Reactant: Nc1ccccc1
Reactant: O=Cc1coc2ccc(Br)cc2c1=O
Solvent: Cc1ccccc1
Product: O=c1c(C=Nc2ccccc2)coc2ccc(Br)cc12
Yield: 98.1 %

Procedure:
A suspension of 6-bromo-3-formylchromone (150 mg; 0.59 mmol) in toluene (10 ml) was heated at 50°-55° C. until the solute had completely dissolved. Aniline (55 μl; 0.59 mmol) was added and the temperature was maintained for 15 minutes. On cooling, a yellow precipitate formed which was filtered off and dried under reduced pressure to give 6-bromo-3-(phenyliminomethyl)chromone (190 mg; 98%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.O>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: O=[N+]([O-])c1cccc(O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc(OCCN2CCOCC2)c1Cl
Reaction time: 15 h
Yield: 84.2 %

Procedure:
2-chloro-3-nitrophenol (1 g, 5.8 mmol) was dissolved in DMF (6 mL). K2CO3 (1.6 g, 11.5 mmol) was added and the solution changed from yellow to red. 4-(2-chloroethyl)morpholine hydrochloride (1.07 g, 5.8 mmol) was added and the solution was allowed to stir for 15 h. The reaction was poured into H2O (30 mL) and extracted with EtOAc (3×30 mL). The organics were washed with 1N NaOH (100 mL) and brine (100 mL) and then dried over MgSO4, filtered, and concentrated in vacuo to provide 4-(2-(2-chloro-3-nitrophenoxy)ethyl)morpholine (1.4 g, 87%) as a golden oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:22][NH:23][NH2:24].[C:25]([O-:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([O-:30])=[O:29]>>[CH3:22][N:23]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[C:8]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])=[CH:11][CH:10]=2)=[N:24]1.[C:25]([O-:32])(=[O:31])/[CH:26]=[CH:27]\[C:28]([O-:30])=[O:29]
Reactant: CN(C)CCNc1ccc(C(=O)c2cccnc2Cl)cc1
Reactant: CNN
Agent: O=C([O-])/C=C\C(=O)[O-]
Product: CN(C)CCNc1ccc(-c2nn(C)c3ncccc23)cc1

Procedure:
By conducting reactions and treatments in the same manner as in Example 42, using 5.8 g of 2-chloro-3-[4-(2-dimethylaminoethylamino)benzoyl]pyridine and 1.2 g of methylhydrazine, converting into the maleate and recrystallizing from ethyl acetate, there was obtained 1-methyl-3-[4-(2-dimethylaminoethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridine·maleate, m.p. 88°-90° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:23]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:24](O)=[O:25])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH:2]([CH3:4])[CH3:3].S(Cl)(C)(=O)=O.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>>[CH3:38][S:39]([NH:42][C:24](=[O:25])[CH:23]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:6]=1)[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)(=[O:41])=[O:40]
Reactant: CS(N)(=O)=O
Reactant: CC(C)Cc1cc(C(C(=O)O)C2CCCCC2)ccc1OCc1ccc2ccccc2n1
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(C(=O)NS(C)(=O)=O)C2CCCCC2)ccc1OCc1ccc2ccccc2n1

Procedure:
The title compound is prepared in analogy to the procedure of Example XVI from 3.5 g (0.008 mol) of the compound of Example 81, 1 g (0.008 mol) of mesyl chloride, 0.912 g of methanesulphonamide, 1.62 g (0.016 mol) of triethylamine and 0.98 g (0.008 mol) of dimethylaminopyridine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])=[CH:6][CH:7]=1.[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)CCC>[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:3]=[N:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[Cl:14])=[CH:6][CH:7]=2)[CH2:18][CH2:17]1
Reactant: OC1CCNCC1
Reactant: Clc1ccc(-c2ccccc2Cl)nn1
Solvent: CCCCO
Product: OC1CCN(c2ccc(-c3ccccc3Cl)nn2)CC1

Procedure:
Operation is carried out in accordance with the methods mentioned for preparing 3-chloro-6-(2-chloro-phenyl)pyridazine (m.p.: 146°-147° C.). 5 g of this product are dissolved in 120 ml of normal butanol and mixed with 6.74 g of 4-hydroxy-piperidine, then heated to reflux. By following the modus operandi described for the previous Example, 5 g of CM 40907 are obtained after recrystallization in absolute ethanol.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@@H:8]([C:34]1[CH:35]=[N:36][CH:37]=[C:38]([O:40][CH2:41][CH3:42])[CH:39]=1)[N:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:18]=2)[C:10]1=[O:33])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH2:41]([O:40][C:38]1[CH:39]=[C:34]([C@@H:8]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[N:18]=3)[C:10]2=[O:33])[CH2:7][C:6]([OH:43])=[O:5])[CH:35]=[N:36][CH:37]=1)[CH3:42]
Reactant: CCOc1cncc([C@H](CC(=O)OC(C)(C)C)N2CCN(CCCc3cccc(NCc4ccc(OC)cc4)n3)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cncc([C@H](CC(=O)O)N2CCN(CCCc3cccc(NCc4ccc(OC)cc4)n3)C2=O)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 20-12 (0.028 g, 0.047 mmol) in dichloromethane (10 mL) was added TFA (1 mL). After 1 hour, the solvent was removed in vacuo and azeotroped twice with toluene (15 mL). The residue was chromatographed (silica gel, 25:10:1:1 followed by 15:10:1:1 ethyl acetate/EtOH/water/NH4OH) to give 20-13 as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19]C)[CH:9]=2)[CH:4]=1.B(Br)(Br)Br>>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2
Reactant: COc1ccc2cc(-c3ccccc3OC)ccc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccccc3O)ccc2c1
Yield: 7 %

Procedure:
The compound is prepared by reaction of 2-methoxy-6-(2-methoxyphenyl)-naphthalene (150 mg, 0.57 mmol, 1 eq) with boron tribromide (8.5 ml, 8.5 mmol, 15 eq) according to method G. Purification by column chromatography with hexane/ethyl acetate as the eluent yields the desired product in a yield of 7%, 9 mg.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([NH:43][C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:50][CH2:51][CH3:52])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:53](I)[CH3:54].[H-].[Na+]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([N:43]([CH2:53][CH3:54])[C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)=[O:42])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:50][CH2:51][CH3:52])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2cccnc2)CC1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N(CC)c2cccnc2)CC1

Procedure:
2-{4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-N-pyridin-3-yl-acetamide (example 127) was treated with ethyl iodide (Aldrich) and sodium hydride to give the title compound. HR-MS (ES, m/z) calculated for C42H50Cl2N7O3 [(M+H)+] 770.3347, observed 770.3347.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[H][H]>[Cr]([O-])([O-])=O.[Cu+2]>[CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4]
Reactant: [H][H]
Reactant: CC(C=O)=Cc1ccccc1
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Product: CC(CO)Cc1ccccc1

Procedure:
α-methylcinnamaldehyde was hydrogenated using copper chromite (2% by weight) as catalyst at a temperature of 150° C. and a pressure of 130° C. psig hydrogen. After the uptake of hydrogen ceased, the mixture was filtered and distilled to obtain the 2-methyl-3-phenylpropanol (b.pt 100° C./1 mm).