Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15](=[NH:17])[NH2:16])=[CH:9][CH:8]=1.[OH:23][CH:24]=[C:25]([CH2:30][CH3:31])[C:26](OC)=O.C([O-])(=O)C.[K+]>C1COCC1>[CH2:30]([C:25]1[C:24](=[O:23])[N:17]=[C:15]([CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:18]=[CH:19][CH:20]=[C:3]([C:2]([F:21])([F:22])[F:1])[CH:4]=3)=[CH:12][CH:11]=2)[NH:16][CH:26]=1)[CH3:31]
Reactant: CCC(=CO)C(=O)OC
Reactant: N=C(N)CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1c[nH]c(CCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)nc1=O
Temperature: 100 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
To a solution of 3-(4-(3-(trifluoromethyl)phenoxy)phenyl)propanimidamide (200 mg, 0.580 mmol) in THF (4 mL) were added methyl 2-(hydroxymethylene)butanoate (151 mg, 0.580 mmol) and potassium acetate (171 mg, 1.740 mmol). The mixture was stirred with a microwave condition at 100° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature; the solvent was removed in vacuo. The residue was purified MDAP to afford the title compound (36.7 mg, 16.29% yield) as a white solid. LCMS: rt=1.67 min, [M+H+]=389.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.ClCCl.Cl.[CH:16]12[O:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][NH:18][CH2:17]2.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:17][CH:16]3[O:23][CH:20]([CH2:21][CH2:22]3)[CH2:19]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: Clc1nc(N2CC3CCC(C2)O3)c2sccc2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
432 mg (2.57 mmol) of thieno[3,2-d]pyrimidine-2,4-diol was chlorinated as above (heat 100° C. overnight in 6.25 mL POCl3) to give 2,4-dichloro-thieno[3,2-d]pyrimidine after the usual workup (removal of toluene, quenching with ice and extraction with dichloromethane followed by drying over MgSO4 and concentration). Thus obtained 2,4-dichloro-thieno[3,2-d]pyrimidine was reacted without any further purification. 2,4-Dichloro-thieno[3,2-d]pyrimidine was dissolved in 25 mL ethanol and 5 mL dichloromethane and 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (384 mg, 2.57 mmol) and 2.1 mL triethylamine (15 mmol, 6 equivalents) were added. After stirring at room temperature for 45 minutes, the mixture was concentrated, dissolved in dichloromethane and washed with sat. NH4Cl, water and sat. NaHCO3. The organic phase was dried over MgSO4 and concentrated to give 626 mg (2.22 mmol, 86% over 2 steps) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2.[OH-].[Na+].[CH3:19]OCCOC.CI>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([CH3:19])[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:5]2
Reactant: COCCOC
Reactant: COC(=O)Cc1ccc2cc(C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Solvent: O
Product: COC(=O)C(C)c1ccc2cc(C)ccc2c1

Procedure:
To a mixture of 22 g. of methyl 6-methyl-2-naphthylacetate, 2.5 g. of sodium hydroxide and 150 ml. of 1,2-dimethoxyethane, 25 g. of methyl iodide are added. The reaction mixture is allowed to stand for several hours and is then diluted with ethanol followed by water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate, filtered, and evaporated to yield methyl 6-methyl-2-naphthyl-α-methylacetate. This derivative is hydrolyzed by treatment with sodium carbonate in aqueous methanol, and the reaction mixture is acidified with hydrochloric acid, washed, dried and evaporated to dryness to yield 2-(6'-methyl-2'-naphthyl)propionic acid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[C:25]([CH2:26]Br)=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]>C(COC)OC.CS(C)=O>[F:19][C:20]1[C:25]([CH2:26][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[C:24]([F:28])[C:23]([F:29])=[C:22]([F:30])[C:21]=1[F:31]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COCCOC
Product: O=C1c2ccccc2C(=O)N1OCc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 64 h

Procedure:
N-hydroxyphthalimide (8.15 g, 0.05 mol) was dissolved in a mixture of dry dimethoxyethane (40 ml) and dry dimethyl sulphoxide (10 ml). To this solution was added, in one portion, potassium carbonate (3.46 g, 0.05 mol). An orange suspension resulted. The pentafluorobenzyl bromide (10.8 g, 0.05 mol) in dry dimethoxyethane (10 ml) was added dropwise over 1 h at room temperature. The reaction mixture was stirred at room temperature for 64 h and then quenched by pouring into water (1 l). The resulting slurry was filtered, the crystals washed with water and dried in vacuo to give N-(pentafluorobenzyloxy)phthalimide as white crystals (15.9)g.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[C:5]([C:11]([F:12])([F:13])[F:14])[CH:4]=1
Reactant: CSc1ccc(C=O)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CSc1ccc(CO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methylsulfanyl-2-trifluoromethyl-benzaldehyde (4.87 mmol) was dissolved in 5 mL of MeOH and the resulting solution was treated with NaBH4 (221.1 mg, 5.84 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the residue was partitioned between CH2Cl2 and 1N HCl solution. The combined extracts were washed with brine, dried over Na2SO4. A small portion of extracts was evaporated to afford the desired product.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([C:20]3[C:21]4[C:26]([CH:27]=[C:28]5[C:33]=3[CH:32]=[CH:31][CH:30]=[CH:29]5)=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:19])[CH2:14][CH2:13]2)[CH2:7]1)=[O:5])C.Cl>O1CCOCC1>[CH:32]1[C:33]2[C:28](=[CH:27][C:26]3[C:21]([C:20]=2[C:18]([N:15]2[CH2:14][CH2:13][CH:12]([N:8]4[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]4)[CH2:17][CH2:16]2)=[O:19])=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: 110 °C
Reaction time: 2.75 h

Procedure:
(3R)-1′-(Anthracene-9-carbonyl)-[1,4′]bipiperidinyl-3-carboxylic acid ethyl ester (containing a small amount of the corresponding isopropyl ester) (10 g, approx. 22 mmol) was dissolved with warming in dioxane (50 mL) and 2N hydrochloric acid (50 mL) was added. The clear yellow solution was heated at 110° C. (slight reflux) and a pinkish red color soon developed. After 165 min the solution was allowed to cool to ambient temperature. After standing overnight the dioxane was evaporated and an oily solid precipitated out. The mixture was washed with dichloromethane and the insoluble oil was separated from the aqueous layer, dissolved in a dioxane-water mixture (100 mL), xylene (100 mL) was added and the mixture was evaporated to dryness, finally under high vacuum, to give the title compound as a yellow foam which was used in the following procedure without further purification.
Reaction SMILES: [C:1]([C:5]([O:7][C:8]([C:10]([F:24])([F:23])[C@@:11](C(=O)C)([C@@H:13]([CH:15]([C:17](=[O:19])[CH3:18])[OH:16])[OH:14])[OH:12])=[O:9])=[O:6])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[C:1]([C:5]([O:7][C:8]([C:10]([F:23])([F:24])[C@@H:11]([C@@H:13]([CH:15]([C:17](=[O:19])[CH3:18])[OH:16])[OH:14])[OH:12])=[O:9])=[O:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)C(O)[C@@H](O)[C@](O)(C(C)=O)C(F)(F)C(=O)OC(=O)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)C(O)[C@@H](O)[C@@H](O)C(F)(F)C(=O)OC(=O)C(C)(C)C
Temperature: -65 °C
Reaction time: 1 h
Yield: 137.7 %

Procedure:
To a solution of 0.5 g (approximately 1 mmol) crude 1-(t-butylcarbonyloxy)-3,5-bis(acetyl)-2-deoxy-2,2-difluororibose in tetrahydrofuran (5 ml) cooled to -65° C. were added 2.0 ml of a 1M solution of potassium t-butoxide in tetrahydrofuran (2 mmol) dropwise and the reaction mixture stirred 1 hour at -65° C. The reaction was then quenched with 0.23 ml of glacial acetic acid (4 mmol) and allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure to give 0.43 gm 1-(t-butylcarbonyloxy)-5-acetyl-2-deoxy-2,2-difluororibose. Mass spec. m/e=390=P+1.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[CH:9]12[CH:18]3[CH2:19][CH:15]([CH:16]=[CH:17]3)[CH:14]1[CH:13]1[CH2:20][CH:10]2[CH:11]([CH:21]=[O:22])[CH2:12]1>>[OH:22][CH:21]([CH:11]1[CH2:12][CH:13]2[CH2:20][CH:10]1[CH:9]1[CH:14]2[CH:15]2[CH2:19][CH:18]1[CH:17]=[CH:16]2)[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: O=CC1CC2CC1C1C3C=CC(C3)C21
Reactant: CC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)CC(O)C1CC2CC1C1C3C=CC(C3)C21
Yield: 93 %

Procedure:
The procedure of Synthesis Example 1 was repeated except that tert-butyl acetate was used instead of 1-ethylcyclopentyl acetate, and 8-tetracyclo[4.4.0.12,5.17,10]-dodecene-3-carbaldehyde was used instead of 5-norbornene-2-carbaldehyde. There was obtained tert-butyl 3-hydroxy-3-(8-tetracyclo[4.4.0.12,5.17,10]dodecen-3-yl)propionate. Yield 93%.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14]>C(OCC)C>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:2][CH3:1])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: CN
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Solvent: CCOCC
Product: CNC1=NC(Cl)=NC(N)N1OC(F)F
Temperature: 22 °C
Reaction time: 8 h

Procedure:
2.9 g (0.093 mol) of methylamine were passed over the course of 20 minutes into a stirred solution of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine in 150 ml of diethyl ether at 0° C. The mixture was stirred at 0° C. for one hour and at 22° C. overnight. Washing with water, drying and concentration yielded 9.4 g (89.5% of theory) of the title compound of melting point 143° C. (decomposition).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([OH:21])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:2]1.[CH3:22][C:23]1([CH3:28])[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:19]([N:24]3[CH2:25][CH2:26][CH2:27][C:23]3([CH3:28])[CH3:22])=[O:21])=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:18])([F:17])[C:13]([F:15])([F:14])[F:16])[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Reactant: CC1(C)CCCN1
Product: CC1(C)CCCN1C(=O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 47 b, using 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (40 mg, 129 μmol) and 2,2-dimethylpyrrolidine (CAN 35018-15-6; 18 μL, 141 μmol) as starting materials and isolated (41 mg, 81%) as light-brown oil; LC-MS (UV peak area, ESI) 100%, 393.1611 [MH+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].O.[OH-].[Li+:19]>O1CCCC1.C(O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:12]([O-:14])=[O:13])=[CH:10][N:11]=2)[CH:8]=1)#[N:2].[Li+:19]
Reactant: CCOC(=O)c1cnc2ccc(C#N)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: N#Cc1ccc2ncc(C(=O)[O-])n2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
Ethyl 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (13.9 g, 65 mmol) and lithium hydroxide monohydrate (2.7 g, 65 mmol) were dissolved in tetrahydrofuran/ethanol/water (1:2:1, 150 mL:300 mL:150 mL). After stirring for 16 hours at ambient temperature, the solvent was removed under vacuum to give lithium 6-cyanoimidazo[1,2-a]pyridine-3-carboxylate (12.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[CH:11][NH:12]3)[CH:5]=[CH:6][CH:7]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:40])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:40])[NH:12]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Brc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To the suspension of 4-(3-bromo-phenyl)-1H-indole (1.48 g, 5.44 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (66 mL) was added pyridinium tribromide (90% purity from Aldrich, 5.80 g, 16.3 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (26 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (1.02 g, 65%) as a tan solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.OO.[NH3:11].[CH3:12][O-:13].[Na+].Cl>CO.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.[CH3:5][CH:4]1[CH2:3][CH2:2][CH2:7][CH2:6][NH:11][C:12]1=[O:13]
Reactant: N
Reactant: C[O-]
Agent: CC1CCCC(=O)C1
Agent: Cl
Agent: OO
Solvent: O
Solvent: CO
Product: CC1CCCCNC1=O

Procedure:
3,3'-Dimethyl-1,1'-peroxydicyclohexylamine (10 g.) derived from 3-methylcyclohexanone, hydrogen peroxide and ammonia, and probably a mixture of stereoisomers was added to a solution of sodium methoxide in methanol (2 g. sodium in 40 c.c. methanol) and the mixture heated under reflux for 2 hours; only a small amount of peroxide remained unreacted. The solution was cooled, diluted with water, neutralised with hydrochloric acid and extracted with chloroform. Distillation of the chloroform extract gave 3-methylcyclohexanone (4.7 g.), methylcaprolactam (4.1 g), b.p. 145°-150°/15 mm., and residue (0.5 g.). Examination of the methylcaprolactam fraction by N.M.R. spectroscopy showed it to be a mixture of 3- and 5-methyl-caprolactam; on storage this fraction crystallized and several recrystallisations yielded the 3-methylcaprolactam, m.p. 87°-100°.
Reaction SMILES: [ClH:1].Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C.O>[ClH:17].[Cl:1][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(Cl)c(N2CCNCC2)c1
Reaction time: 5 h

Procedure:
To a solution of 5.3 g (20 mmol) of 1-(3-Methoxyphenyl)piperazine dihydrochloride in 120 mL of acetic acid and 30 mL of water at 0° C. was added 3.3 g (20 mmol) of N-chlorosuccinimide. After 5 hours, the reaction was concentrated to an oil in vacuo, and the oil was partitioned between ethyl acetate and 1M NaOH. The phases were separated, and the ethyl acetate phase was washed once each with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to an oil in vacuo. The oil was dissolved in a minimum volume of methanol, and the solution was acidified with 2M HCl in ether. The product was isolated by filtration. 1H NMR (D2O, 400 MHz) 7.28 (d, 1H), 6.66 (m, 3H), 3.70 (s, 3H), 3.32 (m, 4H), 3.20 (m, 4H) ppm.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]([OH:14])=O)=[CH:9][C:8]=1[CH3:15])[CH2:4][CH3:5])[CH3:2].CC1(C)[O:21][C@H:20]([CH2:22][O:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30]O)=[NH:29])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH2:19][O:18]1>>[CH2:4]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:14][N:29]=[C:28]([C:27]3[CH:32]=[CH:33][C:24]([O:23][CH2:22][C@@H:20]([OH:21])[CH2:19][OH:18])=[CH:25][C:26]=3[O:34][CH3:35])[N:30]=2)=[CH:9][C:8]=1[CH3:15])[CH2:1][CH3:2])[CH3:5]
Reactant: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(OC[C@@H](O)CO)cc3OC)no2)cc1C
Yield: 24.8 %

Procedure:
The title compound (13 mg) is prepared starting from 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (30 mg, 130 μmol) and (R)-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-2-methoxy-benzamidine (35 mg, 117 μmol) in analogy to Example 197; LC-MS: tR=0.47 min; [M+1]+=448.09.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[F:21][C:22]([F:32])([F:31])[C:23](N1CCOCC1)=[O:24].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:23](=[O:24])[C:22]([F:32])([F:31])[F:21])=[CH:4][CH:3]=1
Reactant: O=C(N1CCOCC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(Cl)ccc1C(=O)C(F)(F)F
Temperature: -50 °C
Reaction time: 2 h

Procedure:
8 g (35 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 105A) are introduced into 100 ml of THF and cooled to −50° C. 55 ml (87 mmol) of butyllithium (1.6N) are added dropwise. After the dropwise addition is complete, the reaction is slowly warmed to −10° C. and kept at 0° C. for 2 h. It is then cooled again to −40° C., and 12.8 g (70 mmol) of 4-(trifluoroacetyl)morpholine (Example 35A), dissolved in 4 ml of THF, are added. The reaction solution is stirred at −40° C. for 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution and extracted. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1). 9 g (79% of theory) of the product are obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21](OCC)[C:22](=[O:38])[CH:23](C=C=O)[N:24]2C(=O)C3=CC=CC=[C:26]3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.CN>ClCCl.CO>[Cl:1][C:2]1[C:20]([N:21]2[CH2:26][C:25](=[O:34])[NH:24][CH2:23][C:22]2=[O:38])=[CH:19][CH:18]=[C:17]([Cl:42])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: CCON(C(=O)C(C=C=O)N1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(COc2cccc3ccc(C)nc23)c1Cl
Agent: CN
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N4CC(=O)NCC4=O)c3Cl)c2n1
Reaction time: 24 h
Yield: 49.8 %

Procedure:
To the solution of 8-[2,6-dichloro-3-[N-ethoxy-carbonylmethyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methylquinoline (527 mg) in dichloromethane (5.3 ml) was added 30% solution of methylamine in methanol (2 ml) at ambient temperature. After stirring for 24 hours, the reaction mixture was evaporated in vacuo. The residue was, purified by flash column chromatography (silica gel 50 ml) eluting with dichloromethane/methanol (20/1, V/V) and by crystallizing from isopropyl ether to give 8-[2,6-dichloro-3-(2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline (187 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[F:19])[N:3]=1.[CH3:20][N:21]([CH3:30])[CH2:22][CH2:23][N:24]([CH3:29])[S:25]([NH2:28])(=[O:27])=[O:26].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:19][C:13]1[C:14]([F:18])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][S:10][C:4]1[N:3]=[C:2]([NH:28][S:25]([N:24]([CH2:23][CH2:22][N:21]([CH3:30])[CH3:20])[CH3:29])(=[O:27])=[O:26])[CH:7]=[C:6]([O:8][CH3:9])[N:5]=1
Reactant: CN(C)CCN(C)S(N)(=O)=O
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)N(C)CCN(C)C)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of example 35 step i) (0.35 g), N-[2-(dimethylamino)ethyl]-N-methylsulfamide (prepared according to procedure outlined in Org. Letts 2004, 6 (16), 2705-2708) (0.18 g), tris(dibenzylideneacetone)dipalladium (0) (73 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (53 mg), cesium carbonate (0.39 g) and dioxane (20 mL). Purification was by reverse phase HPLC (symmetry as the stationary phase and TFA/acetonitrile as the mobile phase) then titurated with MeOH followed by Et2O to give the title compound as a white solid. Yield: 0.12 g
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([O:17][CH3:18])=[O:16].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:15]([O:17][CH3:18])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCCCCC1=O
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CCCCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -5 °C

Procedure:
Methyl 2,2-di(tertiary-butylperoxy)-1-cycloheptanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (12.21 g, 0.1250 mol) to 99% methyl 2-oxo-1-cycloheptanecarboxylate (8.600 g, 0.0500 mol) at room temperature in a three necked 125-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled via a dry ice-acetone bath to −5° C. and 78% sulfuric acid (7.540 g, 0.0600 mol) was added dropwise to the solution with temperature at −5° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for ninety minutes with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4, filtered through a Buchner funnel and analyzed by gas chromatography. The purity was found to be 17%. This product was not purified due to low conversion of product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](OC)=[O:17])=[CH:10][CH:9]=1>C1COCC1>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:12][CH:13]=1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1ccc(O)cc1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a suspension of LAH (22.1 g, 2.5 eq, 583 mmol) in dry THF (1.0 L), was added dropwise a THF (50 mL) solution of methyl 3-(4-hydroxyphenyl)propionate (21 g, 10 eq, 116 mmol) at RT. The reaction mixture was refluxed for 4-5 h. It was worked up by quenching with excess ethyl acetate followed by addition of water (23 mL), 15% aq. NaOH (23 mL) and water (70 mL) under controlled stirring and maintaining RT. To the workup mixture conc. HCl was added to adjust the pH at 7.0. It was then filtered through celite and washed with ethyl acetate. Combined filtrate was dried (Na2SO4) and condensed. Obtained residue was chromatographed (ethyl acetate/hexanes) to obtain 3-(4-hydroxyphenyl)propanol (17 g, 100%) as white solid. Mp: 52-54° C.