Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([OH:38])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13].O>N1C=CC=CC=1>[C:12]([O:15][CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C@H:32]([C:33](=[O:37])[CH2:34]2)[C@:30]2([CH3:31])[C@H:25]([CH2:26][C@@H:27]([O:38][S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:28][CH2:29]2)[CH2:24][CH2:23]3)[CH2:20][CH2:19]1)(=[O:14])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
Acetyl chloride (9.71 ml) was added to a stirred solution of (3β,5α)-3-hydroxypregnane-11,20-dione (97.1 g) [prepared as described by Cameron et al., J. Chem. Soc., 1955, 2807] in methanol (2.4 l) and a solution of bromine (18.5 ml) in methanol (1 l) was then added over 30 min at room temperature. The reaction mixture was poured into water (30 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure to give crude (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g). δ (CDCl3) 0.61 (s,3H), 1.02 (s,3H), 3.00-3.20 (m,1H), 3.49-3.62 (m,2H) and 3.85 (s,2H). Potassium acetate (240 g), potassium iodide (6 g) and glacial acetic acid (250 ml) were added to a solution of (3β,5α)-21-bromo-3-hydroxypregnane-11,20-dione (120 g) in acetone (4.8 l) and the mixture was heated under reflux for 3 h. The reaction mixture was poured into water (50 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. The residue was chromatographed over silica gel and the purified product was crystallised from diethyl ether to give (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) m.p. 163°-165° C.; [α]D +103.3° (c 0.97). 4-Toluenesulfonyl chloride (52 g) was added to a solution of (3β,5α)-21-(acetyloxy)-3-hydroxypregnane-11,20-dione (26 g) in pyridine (260 ml) and the solution was stirred for 4 h at room temperature. The reaction mixture was poured into water (2.6 l) and the precipitated solid was filtered off, washed with water and dissolved in dichloromethane. After drying the solution over sodium sulfate, the solvent was removed under reduced pressure. Crystallisation of the residue from methanol gave (3β,5α)-21-(acetyloxy)-3-{[(4-methylphenyl)sulfonyl]oxy}pregnane-11,20-dione (35 g). m.p. 155°-156° C.; [α]D +62.4° (c 1.11).
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:16]([C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH:15]=[CH2:14]
Reactant: C=CC[Si](C)(C)C
Reactant: OC1(c2ccccc2)CCCCO1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCC1(c2ccccc2)CCCCO1
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 2-phenyltetrahydro-2H-pyran-2-ol (1.066 g, 5.98 mmol) and allyltrimethylsilane (1.901 mL, 11.96 mmol) in CH2Cl2 (25 mL) at 0° C. was added BF3.OEt2 (0.758 mL, 5.98 mmol) dropwise, and the mixture was stirred at the same temperature for 1 hr. Then the reaction was quenched with saturated NaHCO3 and the product was extracted with EtOAc. The extract was washed with brine, and the combined aqueous layers were back extracted with EtOAc once and combined. The extracts were dried over Na2SO4 and evaporated to give an oily residue. It was purified by Combiflash (80 g silica gel) eluting with 1:9 followed by 4:6 EtOAc-hexane to give 2-allyl-2-phenyltetrahydro-2H-pyran as oil (0.954 g). 1H NMR (400 MHz, CCl3D) δ ppm 7.10-7.45 (5H, m), 5.47-5.65 (1H, m, J=17.19, 10.11, 7.33, 7.33 Hz), 4.84-5.00 (2H, m), 3.64-3.78 (1H, m), 3.41-3.57 (1H, m), 2.35-2.48 (1H, m), 2.20-2.35 (1H, m), 1.55-1.81 (4H, m), 1.35-1.54 (2H, m).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:19])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:19][C:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(C(=O)Cl)cc1
Yield: 78.8 %

Procedure:
14.8 g (67 mmols) of ethyl 4-carboxycinnamate, 9.57 g (80 mmols) of thionyl chloride, 100 ml of toluene and 0.18 ml of N,N-dimethylformamide are boiled under reflux for 30 minutes. The reaction mixture is evaporated and the crude product is recrystallised from n-hexane. 12.6 g (79% of theory) of ethyl 4-chloroformylcinnamate are obtained in the form of white crystals; melting point 76.8° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH2:35])[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1>>[NH2:19][C:20]1[C:29]2[N:30]=[C:31]([CH2:36][CH2:37][CH2:38][CH3:39])[N:32]([CH2:33][CH2:34][NH:35][C:8](=[O:9])[C:7]3[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:13]([OH:14])=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=3)[C:28]=2[C:27]2[N:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 56.9 %

Procedure:
Using the general method of Example 92, 3,5-di-(1,1dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol) was reacted with 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.5 g, 1.7 mmol) to provide 0.5 g of N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide as a white powder, m.p. 248-250° C. Analysis: Calculated for C30H40N6O2: %C, 69.74; %H, 7.80; %N, 16.27; Found: %C, 69.65%H, 7.69; %N, 16.42. HRLMS (EI) calcd for C30H40N6O2 (M+) 516.3212 found 516.3226.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:18])=[C:15]([CH2:16][OH:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:17][CH2:16][C:15]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:2]=3[Cl:1])[C:12]=2[O:13][C:14]=1[CH3:18])(=[O:26])[CH3:25]
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Yield: 83.5 %

Procedure:
A mixture of 7-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-2-methylbenzo[b]furan (123 mg), acetic anhydride (43 mg) and pyridine (48 mg) in dichloromethane (5 ml) was refluxed for 2 hours. The reaction mixture was washed with 1N-hydrochloric acid, brine and aqueous saturated sodium bicarbonate, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-acetoxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (115 mg).
Reaction SMILES: [Mg].[CH3:2]I.CN(OC)[C:6]([C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7].Cl>C(OCC)C.BrBr.O1CCCC1>[C:6]([C:8]1[C:16]2[S:15][N:14]=[N:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH3:2]
Reactant: CON(C)C(=O)c1cccc2nnsc12
Reactant: CI
Agent: BrBr
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)c1cccc2nnsc12
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
0.59 g of magnesium turnings in 3 ml of diethyl ether are activated with 1 drop of bromine, and a solution of 1.5 ml of methyl iodide in 5.5 ml of diethyl ether is added dropwise with stirring. When the exothermic reaction has subsided, the mixture is heated and kept for a further 1.5 hours at bath temperature 55° C. The resulting solution is added dropwise under a nitrogen atmosphere and with stirring at -10° C. to the initially introduced solution of 4.9 g of N-methyl-N-methoxybenzo-1,2,3-thiadiazole-7-carboxamide in 150 ml of absolute tetrahydrofuran. After stirring has been continued for 1 hour at -10° C., the mixture is heated and refluxed at bath temperature 75° C. for 6 hours. The reaction mixture is then cooled, poured into ice-water, acidified with 2 N hydrochloric acid and extracted several times using ethyl acetate. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue is purified on silica gel (CHCl3), giving the title compound of m.p. 126°-127° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH2:12]([N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:14](=[O:16])[CH3:15])[CH3:13]
Reactant: CCN(C=Cc1ccccc1)CC
Reactant: CC(=O)OC(C)=O
Product: CCN(C=C(C(C)=O)c1ccccc1)CC

Procedure:
A solution of diethylstyrylamine (1.75 g) in acetic anhydride (5 ml) was heated under reflux for an hour and then distilled under vacuum (0.02 mm) in a bulb-to-bulb apparatus (oven 150° C.). The product was crystallised from ether-petroleum spirit (40°-60° C.) at low temperature, giving crystals of the title product which melted around room temperature.
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:16][CH2:17][CH2:18][CH3:19])([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:20].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([NH2:33])(=[O:32])=[O:31]>C1(C)C=CC=CC=1>[CH2:16]([C:12]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:20])=[C:4]([C:3]2[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:31])(=[O:32])[N:33]=2)[C:13]1=[O:14])[CH2:17][CH2:18][CH3:19]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: CCCCC1(C)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 85.5 %

Procedure:
A solution of Example 27F (0.064 g, 0.191 mmol) and 2-amino-benzenesulfonamide (0.035 g, 0.201 mmol) in toluene (7 mL) was refluxed for 6 hours. The solution was cooled to 25° C. and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane followed by 20% and 30% ethyl acetate in hexane to give the desired product (0.067 g, 86%).
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1)=O.[NH2:29][OH:30]>CO.O>[OH:30][N:29]=[CH:1][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1
Reactant: Cc1c(C=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: NO
Solvent: CO
Solvent: O
Product: Cc1c(C=NO)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reaction time: 8 h
Yield: 78.2 %

Procedure:
To a slurry of 6-formyl-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile (Example 8) (37 mg, 0.1 mmol) in MeOH (1 ml) was added H2NOH (50% wt. in H2O, 14 μl 0.2 mmol) at rt. The heterogeneous mixture was stirred overnight, then diluted with H2O (5 ml) and filtered, the solid was dissolved in MeOH, which was concentrated to give title compound (30 mg, 78%) as a yellow powder. It has a retention time of 6.18 min (standard LCl method, 8 min run). MS Found: (M+H)+=384.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.O>[F:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][N:3]=1
Reactant: CCOc1cnc(Cl)c2ccccc12
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cnc(F)c2ccccc12
Temperature: 145 °C
Yield: 58.8 %

Procedure:
To a solution of 1-chloro-4-ethoxyisoquinolin (4.8 g, 23.12 mmol) in DMSO was added cesium fluoride (6.9 g, 46.24 mmol) at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 145° C. for 18 h. The reaction mass was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (2.6 g, 58.8%) as white solid. MS: MS m/z 192.3 (M++1).
Reaction SMILES: ClC1N=C(N2CCOCC2)C2SC([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=CC=2N=1.C[N:27](C)CCN>>[C:14]([NH2:27])(=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:11][CH:12]=1
Reactant: O=C(O)c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CN(C)CCN
Product: NC(=O)c1ccccc1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with N,N-dimethylethlenediamine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)benzamide. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)-N-(2-dimethylamino)ethyl)benzamide (73 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 16 mg of 340. MS (Q1) 528.0 (M)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[C:10](OCC)(OCC)(OCC)[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.ClCCl>[Br:9][C:4]1[N:3]=[C:2]2[N:1]=[C:10]([CH3:11])[NH:8][C:7]2=[CH:6][CH:5]=1
Reactant: Nc1ccc(Br)nc1N
Reactant: CCOC(C)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1nc2nc(Br)ccc2[nH]1
Temperature: 25 °C

Procedure:
2,3-Diamino-6-bromopyridine (8.16 g) and triethyl orthoacetate (12.0 ml) were mixed in acetic acid (41 ml), and the mixture was refluxed under heating for 29 hr. The mixture was allowed to cool and the solvent was evaporated to give a crude product (10 g). This was dissolved in a sufficient amount of dichloromethane. Anhydrous potassium carbonate and active carbon were added and the mixture was stirred at room temperature. The insoluble matter was filtered off and the solvent was evaporated to give the objective compound (7.59 g) as a pale-yellow powder.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([OH:13])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH2:34][S:33][CH2:32][NH:31]1)[CH3:27]>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:35])[C@@H:30]1[CH:34]([C:11](=[O:13])[CH2:10][CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)[S:33][CH2:32][NH:31]1)[CH3:27]
Reactant: O=C(O)CC1CCc2ccccc21
Reactant: CCOC(=O)[C@@H]1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H]1NCSC1C(=O)CC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
While chilling with ice water, 1.4 g of 2-indanyl-acetic acid and 1.9 g of WSC.HCl were added to 15 ml of methylene chloride, and the mixture was stirred at room temperature for 5 minutes. Then, 1.3 g of L-thioproline ethyl ester dissolved in 10 ml of methylene chloride were added at room temperature, and the mixture was stirred further for 5 hours. The resultant liquid reaction mixture was washed with water, diluted hydrochloric acid and a saturated aqueous solution of sodium bicarbonate in that order. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resultant residue was subjected to column chromatography on silica gel, thereby obtaining 1.45 g (57%) of 3-(2-indanylacetyl)-L-thioproline ethyl ester in the form of colorless oil.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.Br[C:17]([C:24]1[CH:29]=[C:28]([Cl:30])[N:27]=[C:26]([Cl:31])[CH:25]=1)([CH3:23])[CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20]>CCCCCC.O1CCCC1>[Cl:31][C:26]1[CH:25]=[C:24]([C:17](=[CH2:23])[CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])[CH:29]=[C:28]([Cl:30])[N:27]=1
Reactant: CC(Br)(CC(Cl)(Cl)Cl)c1cc(Cl)nc(Cl)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(CC(Cl)(Cl)Cl)c1cc(Cl)nc(Cl)c1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
To a dried tetrahydrofuran solution of 4.03 g of 2,2,6,6-tetramethylpiperidine under N2 was added 17.8 ml of 1.6M n-butyllithium in hexane. The solution was cooled to -75° C. and a concentrated solution of 4-(1-bromo-3,3,3-trichloro-1-methylpropyl)-2,6-dichloropyridine in tetrahydrofuran was added to maintain ≤-65° C. The mixture was stirred at -65° C. for two hours and quenched with 20 mls of water. The organics were extracted with ether, dried (MgSO4), and concentrated in vacuo. The crude product was purified via high pressure liquid chromatography, yielding 5 g (68%), m.p. 66°-67.5° C.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)#[N:6].Cl>C(O)C>[C:5]([C:7]1[C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[NH:15][C:16](=[O:17])[C:11]=2[N:10]=[CH:9][CH:8]=1)(=[O:1])[NH2:6]
Reactant: CCOc1ccccc1-c1nc2c(C#N)ccnc2c(=O)[nH]1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccccc1-c1nc2c(C(N)=O)ccnc2c(=O)[nH]1
Yield: 72 %

Procedure:
30% Aqueous hydrogen peroxide solution (0.5 ml) was added to a stirred aqueous sodium hydroxide solution (1M, 40 ml), followed by 8-cyano-2-(2-ethoxyphenyl)pyrido[3,2-d]pyrimidin-4(3H)-one (Preparation 14; 0.2 g, 0.00068 mol) and ethanol (2 ml). The mixture was heated under reflux for 2 hours, allowed to cool, acidified with 1N hydrochloric acid, and then extracted with a mixture of dichloromethane and methanol (10:1, 5×50 ml). The combined organic fractions were evaporated under vacuum and the resulting residue triturated with ethanol to give the title compound as a colourless solid (0.152 g, 72%), m.p. 295°-297° C. Found: C,61.65; H,4.56; N,17.61. C16H14N4O3 requires C,61.93; H,4.55; N,18.06%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[C:4]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:3]=1.[O:35]=[C:36]([CH3:40])[C:37](Cl)=[O:38]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([S:17]([N:20]3[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]3)(=[O:19])=[O:18])=[CH:15][CH:16]=2)=[C:4]([N:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:37](=[O:38])[C:36](=[O:35])[CH3:40])[CH:3]=1
Reactant: CC(=O)C(=O)Cl
Reactant: O=C(CCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1)c1ccc(Cl)cc1Nc1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)N(c1ccccc1)c1cc(Cl)ccc1C(=O)CCc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 1-(4-chloro-2-phenylamino-phenyl)-3-[4-(4-hydroxypiperidine-1-sulfonyl)-phenyl]propan-1-one (0.200 g) in toluene (20 mL) was added 2-oxopropanoyl chloride (0.427 g). The reaction mixture was heated at 120° C. for 3 h, then stirred at RT overnight to produce N-(5-chloro-2-{3-[4-(4-hydroxypiperidine-1-sulfonyl)-phenyl]-propionyl}-phenyl)-2-oxo-N-phenyl-propionamide, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:34])=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:37])[CH:3]=1.Cl.[NH2:39][OH:40].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:34])=[C:29]([CH:33]=3)[C:30]([OH:32])=[O:31])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:39]\[OH:40])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:37])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(F)c(C(=O)O)c2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Oc2ccc(F)c(C(=O)O)c2)cc1

Procedure:
In analogy to example 151, step 3, 5-{4-[1-(4-chloro-2-methyl-phenyl)-3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-propyl]-phenoxy}-2-fluoro-benzoic acid was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as a colourless solid, MS (ESI−): m/z=533.1 [M−H]−.
Reaction SMILES: [OH-].[K+].Cl[CH2:4][C:5]([C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:6].Cl.CN1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[CH3:26][CH:25]([CH2:10][CH2:9][CH:8]=[C:7]([CH3:12])[CH3:5])[CH2:24][CH2:23][O:27][CH2:4][C:5]([C:7]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:16])=[C:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1)=[O:6]
Reactant: CN1CCCC1=O
Reactant: CC(C)c1cc(C(=O)CCl)cc(C(C)C)c1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CC(C)=CCCC(C)CCOCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Reaction time: 16 h

Procedure:
To a solution of 4.69 g (30 mmol) of 3,7-dimethyl-oct-6-dien-1-ol and 4.21 g (75 mmol) of potassium hydroxide in 150 ml of N-methylpyrrolidone a solution of 3.82 g (15 mmol) of 2-chloro-1-(4-hydroxy-3,5-di-isopropylphenyl)-ethanone in 75 ml of N-methylpyrrolidone is added dropwise at room temperature and under inert atmosphere. After the addition is completed stirring is continued for additional 16 hours. Then the reaction mixture is acidified with 1N HCl and extracted with ethyl acetate. The collected organic phases are washed with water and brine, dried and evaporated. Crystallization of the crude product from hexane gives 2.58 g of compound 109, m.p. 37-39° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1NCCC(C)C)=[O:5])[CH3:2].CS(NC1C=CC2NC(CC(O)=O)=NS(=O)(=O)C=2C=1)(=O)=O.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of cis-2-(3-methylbutylamino)-cyclopentanecarboxylic acid ethyl ester (53.5 mg, 0.237 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 157.4 mg, 0.472 mmol) and a 1.0 M solution of N,N′-dicyclohexylcarbodiimide in dichloromethane (0.47 mL, 0.47 mmol). After stirring at 25° C. for 12 h, the mixture was diluted with dichloromethane and the precipitated N,N′-dicyclohexylurea byproduct was removed by filtration. The filtrate was concentrated and dried in vacuo to afford the crude product, cis-2-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methylbutyl)amino]-cyclopentanecarboxylic acid ethyl ester, which was used in the next step without further purification. LC-MS (ESI) calcd for C23H34N4O7S2 542.19, found 543.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Clc1cccc2cc[nH]c12
Agent: Cl
Solvent: O
Product: Clc1cccc2c(C3=CCNCC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 7-chloroindole (0.70 g, 4.6 mmol) and 4-piperidone hydrochloride hydrate (1.4 g, 9.2 mmol). The product was isolated as a yellow solid. Yield 0.80 g (75%). mp 205-208° C. FDMS m/e=234 (M+ of free base).