Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([F:33])[CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@H]1CCCC[C@@H]1NC>C1(C)C=CC=CC=1.[Cu]I>[F:33][C:21]1[CH:20]=[C:19]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)ccc1OCc1ccccc1
Yield: 36.5 %

Procedure:
A mixture of 4-benzyloxyindole (3.35 g, 15 mmol), 4-bromo-2-fluoro-1-[(phenylmethyl)oxy]benzene (4.22 g, 15 mmol) and potassium phosphate (6.68 g, 31.5 mmol) in toluene (25 mL) was degassed by bubbling argon through the solution for 3 minutes. Copper (I) iodide (143 mg, 0.75 mmol) and (1S,2S)-N,N′-dimethyl-1,2-cyclohexanediamine (426 mg, 0.479 ml, 3.0 mmol) were added and the mixture was refluxed under argon for 24 hrs. After cooling, the mixture was filtered through a plug of silica gel (elution with ethyl acetate) and concentrated. Chromatography (2 columns, elution with 0-50% ethyl acetate in hexane and then a gradient of diethyl ether in hexane) gave the title compound (D1) 2.32 g.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].Br[C:23]1[CH:28]=[C:27]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1[O:33][CH2:34][CH:35]1[CH2:37][CH2:36]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1.O>[CH:35]1([CH2:34][O:33][C:24]2[CH:23]=[CH:28][C:27]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][C:25]=2[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:21])[N:2]([CH3:1])[CH:11]=2)[CH2:36][CH2:37]1
Reactant: CS(=O)(=O)c1ccc(OCC2CC2)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2ccccc2c1=O
Yield: 59.6 %

Procedure:
The title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-1-(cyclopropylmethoxy)-4-methylsulfonylbenzene (6.4 g, 21 mmol), K3PO4 (9.3 g, 43.9 mmol) and Pd(dppf)Cl2 (1.4 g, 1.75 mmol) in a dioxane/water (100 mL/10 mL) mixture were stirred at 60° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA:DCM=1:4). Appropriate fractions were combined and concentrated under reduce pressure. The resultant solid was recrystallized from DCM/MTBE (1:1, 50 mL) to give the title compound (4.0 g, 60%) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.51 (dd, J1=8.0 Hz, J2=0.8 Hz, 1H), 7.98 (dd, J1=8.4 Hz, J2=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 7.53 (m, 2H), 7.16 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 3.88 (m, 2H), 3.66 (s, 3H), 3.09 (s, 3H), 1.02-0.98 (m, 1H), 0.44-0.38 (m, 2H), 0.11-0.09 (m, 2H). LCMS: 384.1 (M+H)+
Reaction SMILES: [CH:1]1([N:4]([CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH2:18][CH3:19])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=1>>[CH:1]1([N:4]([CH:20]2[CH2:21][CH2:22][N:23]([C:27]3[N:32]=[CH:31][C:30]([CH2:33][CH3:34])=[CH:29][N:28]=3)[CH2:24][CH2:25]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH2:18][CH3:19])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Reactant: CCc1cnc(Cl)nc1
Product: CCc1cnc(N2CCC(N(C(=O)c3cnc(-n4ccnc4CC)nc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from 2-(2-ethyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide and 2-chloro-5-ethylpyrimidine following a procedure analogous to that described in Example 3. LC (method 10): tR=1.46 min; Mass spectrum (ESI+): m/z=447 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:19]=[C:20]([C:24]([NH:27]C(=O)C)=[CH:25][CH:26]=3)[C:21]([O-:23])=[O:22])[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[K+]>O.[OH-].[K+]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:24]([NH2:27])=[C:20]([C:21]([OH:23])=[O:22])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3ccc(NC(C)=O)c(C(=O)[O-])c3)cs2)cc1OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(-c2nc(-c3ccc(N)c(C(=O)O)c3)cs2)cc1OCC
Yield: 20.3 %

Procedure:
A solution of 1 g of potassium 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-6-acetylaminobenzoate in 50 ml of water and 10 ml of 30% potassium hydroxide was refluxed for 8 hours with heating. After the completion of a reaction, the solvent was removed by distillation. The residue was made weakly acidic with 10% hydrochloric acid and extracted with 80 ml of ethyl acetate. The extract was washed with 20 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethyl acetate to obtain 168 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-aminophenyl)thiazole.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:11]=[N:12][C:13]([NH2:25])=[C:14]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH:15]=2)[CH:5]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[NH2:25][C:13]1[N:12]=[CH:11][C:10]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:26])=[O:2])=[CH:15][C:14]=1[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: COC(=O)c1cccc(-c2cnc(N)c(-c3nc4ccccc4s3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cccc(C(=O)O)c2)cc1-c1nc2ccccc2s1
Temperature: 50 °C

Procedure:
To a solution of 3-(6-amino-5-benzothiazol-2-ylpyridin-3-yl)-benzoic acid methyl ester (0.980 g, 2.7 mmol) in dioxane/H2O (5:1, 30 mL) was added K2CO3 (1.5 g, 11 mmol), and the mixture was heated at 50° C. for 16 h. Evaporation of the solvents and neutralization with acetic acid gave a precipitate that was filtered off and dried in vacuo to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ=7.51-7.66 (m, 3H), 7.95-8.00 (m, 2H), 8.14-8.18 (m, 4H), 8.24 (d, J=8.4 Hz, 2H), 8.29 (d, J=1.8 Hz, 1H), 8.61 (d, J=2.1 Hz, 1H). MS(ES+): m/z=348.06 (100) [MH+]. HPLC: tR=3.42 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[O:21][CH3:22].CC1C=CC(S(O[CH2:34][CH2:35][CH:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:45]([O:44][C:42]([N:39]1[CH2:40][CH2:41][CH:36]([CH2:35][CH2:34][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:20])[N:7]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH:8]=[N:9]3)=[CH:4][C:3]=2[O:21][CH3:22])[CH2:37][CH2:38]1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
A suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7 g, 23 mmol), (prepared as described for the starting material in Example 12), 4-(2-(4-methylphenylsulphonyloxy)ethyl)-1-tert-butoxycarbonylpiperidine (11.4 g, 30 mmol) in DMF (70 ml) containing potassium carbonate (6.32 g, 46 mmol) was stirred at 100° C. for 3 hours. After cooling, the volatiles were removed under vacuum and the residue was partitioned between ether and water. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The solid was triturated with pentane, filtered and dried under vacuum to give 7-(2-(1-tertbutoxycarbonylpiperidin-4-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (10.5 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH2:9])=[C:4]([O:10][CH3:11])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:10][CH3:11])=[C:5]([NH2:9])[CH:6]=1
Reactant: COc1cc(Cl)c(I)cc1N
Reactant: OB(O)c1cc(Cl)ccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(Cl)c(-c2cc(Cl)ccc2Cl)cc1N
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.2 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzenamine (4.1 g, 14.5 mmol), 2,5-dichlorophenylboronic acid (3.3 g, 17.4 mmol), Pd(PPh3)4 (500 mg, 1.45 mmol) and Na2CO3 (4.7 g, 43.5 mmol) in 1,4-dioxane (150 mL) and water (15 mL) was stirred at 80° C. under argon for 16 h. The mixture was allowed to cool to room temperature, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=20:1) to afford the desired product (3.3 g, 75.8% yield) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([NH:12][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1CNC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
2-Nitrobenzaldehyde (1 g, 6.61 mmol) and 4-amino-1-benzylpiperidine (1.35 mL, 6.61 mmol) were combined in ethanol (20 mL). The resulting suspension was stirred at room temperature for 20 min before a solution of sodium borohydride (0.25 g, 6.61 mmol) in ethanol (5 mL) was added dropwise over 10 min. After the addition was complete, the reaction was stirred for 1 h, cooled to 0° C. and concentrated ammonium chloride was added to the reaction mixture until no bubbling was observed. The solvents were evaporated in vacuo and the resultant crude mixture was dissolved in water (10 mL) and methylene chloride (10 mL). The layers were separated and the organic layer washed with water (2×) and brine (2×), dried over sodium sulfate, filtered, and concentrated to afford 1.5 g (70%) of the desired product. LC/MS: tR=0.7 min, 326.18 (MH)+.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[CH:6][CH2:5]2)[O:3]C1>C(OCC)(=O)C>[F:17][C:11]1[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:7]1[CH2:6][CH2:5][C:4](=[O:3])[CH2:9][CH2:8]1
Reactant: Fc1cccc(C2=CCC3(CC2)OCCO3)c1F
Solvent: CCOC(C)=O
Product: O=C1CCC(c2cccc(F)c2F)CC1
Temperature: 25 °C
Reaction time: 43 h
Yield: 53.3 %

Procedure:
First, 39.4 g of 4-(2,3-difluorophenyl)-3-cyclohexenone ethylene ketal, 150 ml of ethyl acetate, and 1.0 g of 10% palladium catalyst(Pd-C) were placed in a 500 ml autoclave. The mixture was stirred at room temperature for 43 hours under a hydrogen pressure of 10 kg/cm2. A catalyst was filtered away and a filtrate was concentrated. Thereafter, 225 ml of 1,4-dioxane, 675 ml of water, and 1 g of p-toluenesulfonic acid monohydrate were added to the residue. The mixture was stirred under reflux for 2 hours. The reaction mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=19:1) and distilled under reduced pressure to obtain 17.5 g of 4-(2,3-difluorophenyl)cyclohexanone (Y: 72%). The compound thus obtained had a purity of 98.9% by GC and a b.p. of 125° C. to 128° C./0.6 mmHg.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15].[H-].[Na+]>CN(C=O)C>[C:14]([CH:16]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([CH3:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18])#[N:15]
Reactant: CC(C)c1nnc2ccc(Cl)nn12
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc2nnc(C(C)C)n2n1
Temperature: 0 °C
Reaction time: 14 h
Yield: 16.7 %

Procedure:
6-Chloro-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (5.00 g, 25.4 mmol, Preparation #G.1) and ethyl 2-cyanoacetate (3.16 g, 28.0 mmol) were added to DMF (50 mL) then the solution was cooled to about 0° C. Sodium hydride (60% in oil, 1.22 g, 30.5 mmol) was added then the mixture was stirred for about 5 min at ambient temperature and at about 60° C. for about 14 h. The mixture was cooled to ambient temperature then concentrated under reduced pressure. The residue was stirred with EtOAc (100 mL) and 2N HCl (50 mL) for about 10 min and the insoluble material was collected by filtration and dried to give the title compound (1.16 g, 17%): LC/MS (Table 1, Method g) Rt=1.53 min; MS m/z: 273.9 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>CC(C)=O>[C:6]([O:5][C:3](=[O:4])[CH2:2][O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([Br:16])[CH:18]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.8 %

Procedure:
Tert-butyl bromoacetate (1.88 mL, 12.69 mmol) and potassium carbonate (3.5 g, 25.38 mmol) were added to a solution of 3-bromophenol (2.09 g, 12.08 mmol) in acetone (30 mL), and the mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The mixture was filtered, and the filtrate was evaporated to dryness to give (3-bromophenoxy)acetic acid tert-butyl ester as a colorless oil (3.53 g, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6].[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O>[N:26]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:25])([CH3:24])[C@@H:11]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:7])=[O:6])=[N+:27]=[N-:28]
Reactant: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, methyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (24a) (0.62 g, 1.6 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.24 g (3.2 mmol) of sodium azide (NaN3). After work-up, the crude material (24b) was used in the next step without further purification. MS (ESI) m/z 421.96 (M+Na)+.
Reaction SMILES: [C:1]([C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[ClH:22]>O1CCCC1.C(O)C>[ClH:22].[NH2:2][CH2:1][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:13][CH3:14])[CH2:4]1
Reactant: COc1cccc2c1CCC(C#N)=C2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCC(CN)C2

Procedure:
A solution of the compound obtained in step (v) above (9.2 g, 0.05 mol) in anhydrous tetrahydrofuran (150 ml) is added dropwise to a mixture of lithium aluminum hydride (3.8 g, 0.1 mol) and anhydrous tetrahydrofuran (50 ml) under nitrogen atmosphere. The reaction mixture is heated to the reflux temperature for 4 hours, and then cooled. Water (40 ml) is added thereto and the reaction mixture is extracted with ethyl acetate (2×300 ml). The organic phase is dried over sodium sulfate, filtered and concentrated to dryness. The residue is then purified by flash chromatography eluting with methanol/ammonia 97/3. The hydrochloride is prepared by treating the thus obtained free base with HCl saturated isopropanol. The product of the title (9 g) is thus obtained; m.p.231°-232° C. (ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=1>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)=[CH:31][C:32]=1[C:37]([F:38])([F:39])[F:40]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(OCc3ccc(Cl)c(C(F)(F)F)c3)ccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a solution of tert-butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.053 g, 0.183 mmol) in DMF (1 mL) was added Cs2CO3 (0.0.071 g, 0.219 mmol) followed by 4-(bromomethyl)-1-chloro-2-(trifluoromethyl)benzene (0.050 g, 0.183 mmol). The reaction was stirred at 60° C. for 16 h. The mixture was filtered. The filtrate was concentrated under vacuum and purified by silica gel column chromatography to give the title compound as a white solid (0.048 g). LCMS m/z=480.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H), 2.21-2.34 (m, 1H), 2.50 (dd, J=15.73, 8.40 Hz, 1H), 2.73 (dd, J=15.79, 6.32 Hz, 1H), 2.81-2.93 (m, 1H), 3.64-3.77 (m, 1H), 3.94-4.05 (m, 1H), 4.06-4.17 (m, 1H), 5.10 (s, 2H), 6.84 (dd, J=8.72, 2.40 Hz, 1H), 7.07 (d, J=2.40 Hz, 1H), 7.13 (d, J=8.72 Hz, 1H), 7.47-7.53 (m, 1H), 7.55-7.61 (m, 1H), 7.79 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[C:4]([C:18]([F:21])([F:20])[F:19])[N:3]=1.[NH:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>>[N:22]1([C:2]2[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23]1
Reactant: c1cc[nH]c1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cccc3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example A.2) (0.16 g, 0.5 mmol) and commercially available pyrrole (0.067 g, 1.0 mmol) according to the general procedure IVa. Obtained as an off-white solid (0.04 g, 22%). MS (EI) 357.0 [(M)+]; mp 120.5° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]([CH3:17])=[CH:5][CH2:6][CH2:7][CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9](=[O:11])[CH3:10].CC(C)=O.C(O)(=O)C>C(O)C>[CH3:17][C:4]([CH3:3])=[CH:5][CH2:6][CH2:7][CH:8]([CH:9]([OH:11])[CH3:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(CCC=C(C)C)C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)C(CCC=C(C)C)C(C)O
Reaction time: 0.25 h

Procedure:
Sodium borohydride (22.9g, 0.605 mol) was added portionwise over a 1h period to a cold (0° C.) solution of 7-methyl-3-carboethoxy-6-octen-2-one (42.4g, 0.2 mol, which may be prepared as described by Cl. Daessle, H. Favre, and H. Schinz, Helv. Chim. Acta, 40:2278 (1957)) in ethanol (424 mL). The mixture was allowed to rise to 25° C. over a 0.5h period. After the mixture was stirred at 25° C. for 3.5h, acetone (50 mL) was added dropwise over a 15 min period. After stirring the mixture for 15 min, 25% aqueous acetic acid (200 mL) was added cautiously. The mixture was concentrated under reduced pressure to about 250 mL. The residue was diluted with water (150 mL) and extracted with methylene chloride (3×250 mL). The extracts were washed with water (2×100 mL) brine (100 mL) and dried over sodium sulfate. Evaporation of solvent produced 45.4g of crude product. A sample of the crude was kugelrohr distilled (0.5 mm, 150° C. bath temp.) to provide a sample for analysis of ethyl 2-(4-methyl-3-pentenyl)-3-hydroxybutyrate 2(GLC purity: two isomers; 50.9% and 43.1%). NMR (CDCl3, 60 MHz) δ 1.2 (3H, d, J=7Hz), 1.23 (3H, t, J=7Hz), 1.58 (3H, s), 1.67 (3H, s), 1.0-2.8 (5H, m), 3.6-4.1 (1H, m), 4.17 (2H, q, J=7Hz), 4.9-5.3 (1H, m); IR (film) vmax 330, 2960, 2910, 30, 1450 cm-1 ; MS m/e 214, 199, 181, 143, 99, 82. Both isomers display similar mass spectra. The abbreviation Et as used herein represents --CH2CH3.
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.[CH2:16]([Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])Cl)[CH3:17]>CN(C)C=O>[CH3:10][C:2]([O:1][Si:18]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:16][CH3:17])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)CCCC
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCC(C)(CCCC)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 19 h
Yield: 94.7 %

Procedure:
A solution of 175.8 g of 4-hydroxy-4-methyl-1-octyne (U.S. Pat. No. 4,233,231 ), 112.1 g of imidazole and 625 ml of dry dimethylformamide (DMF) was stirred under dry nitrogen and 207.9 g of triethylchlorosilane added. The resulting homogenous solution was stirred at 50°-55° for 19 hours, then cooled to 25° C. and partitioned between hexane and water. The hexane layer was washed three times with water, then dried over anhydrous magnesium sulfate (MgSO4), and hexane evaporated in vacuo. The concentrate was distilled to yield 94.7% of the title compound as a colorless liquid, bp 60°-61° C. (0.20 mm Hg).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:37]([C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:27]=[CH:28][CH:29]=3)=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, yellow solid (106 mg, 88%), MS (ISP) m/z=482.3 [(M+H)+], mp 169° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and quinoline-4-carboxylic acid.