Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[C:4](F)[CH:3]=1.C(NC([O:23][CH2:24][CH3:25])=O)C.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][C@H:11]([CH3:13])[O:10][C@H:9]([CH3:14])[CH2:8]2)=[C:4]([O:23][CH2:24][CH3:25])[CH:3]=1
Reactant: C[C@@H]1CN(Cc2ccc(Br)cc2F)C[C@H](C)O1
Reactant: CCNC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1cc(Br)ccc1CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 100 °C
Yield: 13.9 %

Procedure:
To a solution of cis 4-(4-bromo-2-fluorobenzyl)-2,6-dimethylmorpholine (0.76 g, 2.5 mmol) in 1,4-dioxane (7.5 mL) under nitrogen was added ethyl urethane (1.2 mL, 10.0 mmol) followed by portionwise addition of sodium hydride (60% dispersion in mineral oil, 0.40 g, 10.0 mmol). The reaction mixture was heated at 100° C. for 24 h then partitioned between DCM and water and the phases were separated. The aqueous phase was further extracted with DCM and the combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, 80 g column, ISCO, 0-100% ethyl acetate in pentane) to afford the title compound (0.114 g, 14%). 1H NMR (CD3OD and CDCl3, 300 MHz): 7.22 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1, 1.9 Hz, 1 H), 6.97 (d, J=1.9 Hz, 1H), 4.01 (q, J=7.0 Hz, 2H), 3.75-3.62 (m, 2H), 3.47 (s, 2 H), 2.75-2.66 (m, 2H), 1.86-1.76 (m, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.14 (d, J=6.3 Hz, 6H). LCMS (Method G): RT=3.24 min, M+H+=328.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[F:10])([OH:29])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(Br)c(F)c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(Cc3ccccc3)CC2)c(F)c1
Temperature: 0 °C

Procedure:
To a stirred and cooled (0° C.) solution of 4-bromo-3-fluoroanisole (1 g; 4.88 mmol) in anhydrous THF (7 mL) was added isopropyl magnesium chloride (2.0M in THF; 2.22 mL; 4.43 mmol) dropwise. The reaction was stirred at room temperature for 30 min and then cooled to 0° C. 1-benzyl-4-piperidone (0.72 mL; 4.03 mmol) was added dropwise and the reaction was stirred at room temperature for 14 h. The reaction was quenched with saturated NH4Cl and partitioned between EtOAc (50 mL) and H2O (30 mL). The aqueous layer was extracted with EtOAc (3×50 mL) and the combined extracts were washed with brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-50% EtOAc/hexanes gradient) to afford 1-benzyl-4-(2-fluoro-4-methoxyphenyl)piperidin-4-ol as a light orange solid. LCMS=315.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.38-7.31 (m, 5H), 7.28-7.24 (m, 1H), 6.66 (dd, J=8.7, 2.5 Hz, 1H), 6.61 (dd, J=14.4, 2.5 Hz, 1H), 3.79 (s, 3H), 3.56 (s, 2H), 2.77 (br d, J=10.6 Hz, 2H), 2.54-2.48 (m, 2H), 2.31-2.24 (m, 2H), 1.84 (d, J=12.3 Hz, 2H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=2)[N:11]=1.[Li+].[OH-]>C1COCC1.CCOC(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH:18]=2)[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A solution of N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, (0.050 g, 0.077 mmol) in THF was treated with LiOH (0.5 mL, 1.0M) at 60° C. After 5 min, at 120° C., the solution was diluted with EtOAc, and washed with brine, filtered and concentrated in vacuo. Preparative HPLC provided the desired compound, 555, as a racemic mixture of trans isomers (12 mg, 33% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][CH:21]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][OH:35])=[CH:29][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23].[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47](O)=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:35][CH2:34][CH2:33][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][CH:21]([Cl:20])[C:22]([O:24][CH3:25])=[O:23])=[CH:32][CH:31]=2)=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)C(Cl)Cc1ccc(CCO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Triphenylphosphine (2.4 g, 9 mmol) was added to a solution of methyl 2-chloro-3-[4-(2-hydroxyethyl)phenyl]propanoate (2.1 g, 8.5 mmol) and 4-(benzyloxy)phenol (1.7 g, 8 mmol) in 20 ml toluene under nitrogen atmosphere. The solution was warmed to 55° C. and diisopropyl azodicarboxylate (1.8 g, 9 mmol) was added. The reaction mixture was stirred at 55° C. overnight. The mixture was allowed to cool and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography using a 80:20 mixture of heptane and EtOAc as eluent to yield 2.28 g of the desired product (yield 61%) as colourless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15]/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[F:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[CH2:15][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:19][CH:20]=1
Reactant: Fc1ccc(/C=C/CBr)cc1
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(OC/C=C/c2ccc(F)cc2)c(C)c(C)c1NC=O
Yield: 52 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-[(E)-3-bromo-1-propenyl]-4-fluorobenzene, the title compound was synthesized according to Reference Example 17b. Yield: 52%. Melting point: 196-198° C. (Ethyl acetate-hexane)
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][C:10]1[N:25]=[C:13]2[CH:14]=[CH:15][CH:16]=[C:17](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:12]2[N:11]=1.O>CS(C)=O>[CH3:9][C:10]1[N:25]=[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([CH:18]3[CH2:4][CH:19]3[C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:12]2[N:11]=1
Reactant: CCOC(=O)/C=C/c1cccc2nc(C)nn12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1CC1c1cccc2nc(C)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a suspension of sodium hydride (0.950 g, 24.8 mmol) in dimethyl sulfoxide (82 mL) was added a solution of trimethylsulfoxonium iodide (4.77 g, 21.8 mmol) in dimethyl sulfoxide (35 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added a solution of ethyl (2E)-3-(2-methyl[1,2,4]triazolo[1,5-a]pyridin-5-yl)acrylate (4.20 g, 18.2 mmol) in dimethyl sulfoxide (100 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (1.80 g, yield 40%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@@H:6]1[N:24]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>[Ni].C(OCC)(=O)C>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[NH2:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](N)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 60.9 %

Procedure:
To a mixture of about 3.0 grams of 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl azide, 0.5 grams Raney nickel catalyst, and 40 ml. ethyl acetate, is vigorously agitated with hydrogen at atmospheric pressure, at a temperature of about 25° C. for a period of about 6.5 hours. The reaction mixture is filtered through diatomaceous silica, and the filtered solution is evaporated in vacuo to a syrup which crystallizes upon standing at a temperature of about 5° C. The crystalline product is recrystallized from 2-propanol to give about 1.7 grams of 2,3,4,6-tetra-O-acetyl-β-D-mannopyranosylamine; m.p. 145°-147° C.; [α]D25 -9.8° (c 1.02, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:7]([OH:19])[CH2:6]1)=[O:4].[CH3:20]I>ClCCl.[Ag-]=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@H:7]([O:19][CH3:20])[CH2:6]1)=[O:4]
Reactant: CI
Reactant: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)C1
Agent: O=[Ag-]
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](OC)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of alcohol (d) (6.5 g, 24 mmol), silver(I) oxide (16.5 g, 72 mmol), methyl iodide (4.5 ml) and 3 A molecular sieves (10 g) in dichloromethane (100 ml) was stirred at room temperature for 18 hours. The mixture was filtered and evaporated. The residue was chromatographed on silica eluting with 1:2 ethyl acetate:petrol affording an oil (5.47 g, 80%).
Reaction SMILES: [C:1]([N:8]([CH3:34])[C@H:9]([C:31](O)=[O:32])[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:31](=[O:32])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:15])[N:8]([C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])[CH3:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: CN(C(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1

Procedure:
This compound is prepared using Procedure C. Nα-Boc-Nδ-Fmoc-Nα-methylornithine (100 mg) was coupled with benzylamine to afford titled compound (50 mg) as a glassy solid: 1H NMR (400 MHz, CDCl3) δ1.42 (s, 9H), 1.52 (m, 2H), 1.70 (m, 2H), 2.80 (s, 3H), 3.26 (m, 2H), 4.18 (m, 1H), 4.22 (m, 1H), 4.41 (m, 2H), 4.61 (m, 2H), 7.31 (m, 7H), 7.43 (m, 2H), 7.63 (m, 2H), and 7.81 (m, 2H).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.Cl[P:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]3[CH:21]=[CH:22][CH:23]=[C:13]([C:14]=23)[O:12]1.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][NH:3][P:11]1[O:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]3[CH:21]=[CH:22][CH:23]=[C:13]([C:14]=23)[O:12]1
Reactant: CCN(CC)CC
Reactant: ClP1Oc2cccc3cccc(c23)O1
Agent: CN
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CNP1Oc2cccc3cccc(c23)O1
Temperature: 5 °C

Procedure:
Under a nitrogen atmosphere, 0.4 ml triethylamine was added to 1.5 ml methylamine (2 M in THF) in 20 ml dry toluene. To the resulting solution was cooled to 5° C. and 250 mg 2-chloronaphtho[1,8-de][1,3,2]dioxaphosphinine (available from Hansa Fine Chemicals GmbH, Bremen, Germany) was slowly added. After stirring overnight at room temperature 20 ml hexane was added. The precipitate was removed by centrifugation. The solvents were removed under vacuum. The product N-methylnaphtho[1,8-de][1,3,2]dioxaphosphinine-2-amine was isolated as an oil and used as such. 31P-NMR C6D6 δ 121.2.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1(CCC2C=CC=CC=2)C=CC=CC=1.C1(CCC2C=CC(S(Cl)(=O)=O)=CC=2)C=CC(S(Cl)(=O)=[O:40])=CC=1.ClS(O)(=O)=O>>[C:1]1([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([S:7]([OH:40])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc(CCc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(CCc2ccc(S(=O)(=O)Cl)cc2)cc1
Agent: O=S(=O)(O)Cl
Solvent: c1ccc(CCc2ccccc2)cc1
Product: O=S(=O)(O)c1ccc(CCc2ccccc2)cc1

Procedure:
Polybibenzyl sulfone homopolymers are prepared by heating bibenzyl- 4 -sulfonyl chloride in the presence of a catalytic amount of an anhydrous Lewis acid, or by using a stoichiometric mixture of bibenzyl and bibenzyl- 4,4' -disulfonyl chloride as hereinafter described. The preparation of the homopolymer first necessitates the synthesis of either the mono or di sulfonyl chloride derivative of bibenzyl. Bibenzyl- 4 -sulfonyl chloride may be prepared by a three step procedure by treating bibenzyl in solution with approximately equi molar quantities of chlorosulfonic acid to form bibenzyl- 4 -sulfonic acid followed by neutralization in an aqueous medium using sodium or barium hydroxide to yield the sodium or barium salt which is in turn treated in a solvent with an acid halide such as thionyl chloride to yield bibenzyl- 4 -sulfonyl chloride. Another suitable technique for the preparation of the monosulfonyl chloride derivative involves the treatment of the free sulfonic acid derivative of bibenzyl in a solvent with a complex of phosgene and a tertiary organic amide.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1F.[C:16]([O:23][CH3:24])(=[O:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].Cl>CN1CCCC1=O.O>[Cl:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[CH:17]([C:16]([O:23][CH3:24])=[O:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC(=O)C(C(=O)OC)c1cc(OC)c([N+](=O)[O-])cc1Cl
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
Sodium hydroxide (4.49 g, 112.3 mmol) was added at room temperature to a stirred solution of 1-chloro-2-fluoro-4-methoxy-5-nitrobenzene (11.0 g, 53.5 mmol) and dimethyl malonate (8.976 g, 67.9 mmol) in N-methylpyrrolidinone (110 mL). The mixture was heated to 80° C. for 2 hours then cooled to 5° C. The pH of the mixture was adjusted to 2 using aq. 1N HCl solution then water (600 mL) was added gradually with stirring over 15 minute at 5° C. The precipitated solid was collected by filtration and washed with water (2×20 mL). The filtered solid was dissolved in dichloromethane (150 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound (15.5 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[CH2:9][CH2:8][CH:7]=[C:6]([CH3:10])[CH2:5][CH2:4][CH:3]=1.CC1CCC(C)=CCCC=1.[BrH:21]>>[CH3:10][C:6]12[CH:3]([Br:21])[C:2]([CH3:1])([CH2:4][CH2:5]1)[CH2:9][CH2:8][CH2:7]2
Reactant: CC1=CCCC(C)=CCC1
Reactant: Br
Agent: CC1=CCCC=C(C)CC1
Product: CC12CCCC(C)(CC1)C2Br
Yield: 93.3 %

Procedure:
A mixture of 68 g (0.5 mol) 1,5-dimethyl-1,5-cyclooctadiene and 1,6-dimethyl-1,5-cyclooctadiene (ratio 80/20) was boiled under stirring for 1 hour with 500 ml 48% hydrogen bromide and 10 g of AMBERLYST A15 ion-exchange resin. Thereafter, the reaction product was subjected to azeotrope distillation with the aqueous hydrogen bromide solution. The distillate was then extracted with pentane. The pentane layer was treated as described in Example 1a. By fractional distillation under reduced pressure 81 g 1,5-dimethyl-8-bromobicyclo[3,2,1]octane (b.p. 93° C./10 mm Hg) was obtained in 93.3% yield. The purity of the product according to gas-liquid chromatography was more than 98%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH2:13])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[CH3:25][CH:26]([S:28](Cl)(=[O:30])=[O:29])[CH3:27].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[NH:13][S:28]([CH:26]([CH3:27])[CH3:25])(=[O:30])=[O:29])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Nc1ccsc1-c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 22 h
Yield: 43985.1 %

Procedure:
Charge a double jacketed 20 L reactor equipped with mechanical stirrer and set under inert atmosphere of argon with 2-(4-Bromo-phenyl)-thiophene-3-ylamine (562 g, 2.21 mol) and CH2Cl2 (9.435 L). Obtain a clear solution. Add DBU (1.999 L) and cool the mixture to 9.4° C. Add propane-2-sulfonyl chloride (0.616 g) in 20 minutes maintaining the temperature below 25° C. Stir the reaction mixture 22 h at 20° C. After completion of reaction, cool the reaction mixture to 11° C. and add an aqueous solution of satd. aq. NH4Cl (7.65 L) cooled at 10° C. in 5 minutes. Heat the mixture to 20° C. and separate the aqueous phase. Wash the organic layer with 2N HCl (5.12 L), evaporate to dryness and take the residue into ethyl alcohol (800 g) . Heat the mixture until complete dissolution at 70° C. Cool the solution to 41° C. and add water (1384 mL). Stir the suspension overnight at 22° C., filter and wash two times with 254 mL of a 1/1 EtOH/H2O mixture. Dry the resulting beige solid under vacuum at 26° C. for 4 days to give propane-2-sulfonic acid[2-(4-bromo-phenyl)-thiophene-3-yl]-amide (688 g, 1.9 mol). 1H NMR (250 MHz, CDCl3): 1.25(d,6 H, J=6.9 H), 3.16 (hept, 1 H, J=6.9 Hz), 7.28(pseudo s, 2 H), 7.33(d, 2 H, J=8.5 Hz), 7.6(d, 2 H, J=8.5 Hz)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O>C(O)(=O)C.CCO>[Cl:12][C:13]1[C:20]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[N:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1Cl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 2-chloro-3-(trifluoromethyl)benzaldehyde (0.42 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.64 g, in 93% yield, mp: 261.5° C. 1H NMR (CD3OD) δ 8.89 (s, 1H), 8.51 (d, 1H), 7.85 (m, 3H), 7.56 (t, 1H), 6.89 (d, 2H). 13C NMR (CDCl3) δ 166.9, 163.1, 144.3, 135.7, 132.8, 132.5, 131.0, 130.3, 130.1, 128.5, 125.4, 124.3, 123.2, 116.4. Anal. Calcd for C15H10ClF3N2O2. ½H2O: C, 51.22; H, 2.86; N, 7.96; CI, 10.08; F, 16.20. Found: C, 51.17; H, 3.04; N, 7.53; CI, 10.25; F, 15.93.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][CH:13](O)[C:12]=2[CH:18]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:15][CH2:14][CH:13]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12]=2[CH:18]=1
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)C(O)CCO2
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)C(N1CCCCC1)CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methane sulfonyl chloride (14.9 ml) is added dropwise to a stirred solution of the product obtained in Step 1. (31.6 g) and triethylamine (29.3 ml) in methylene chloride (750 ml) cooled to 0° C. under nitrogen. The reaction mixture is stirred at RT for 21/2 hours and cooled to 0° C. Piperidine (175 ml) is added to the cooled reaction mixture and the solution stirred at RT overnight. Sat'd aq. sodium bicarbonate is added to the solution and the mixture is stirred for 30 minutes. The organic layer is separated, washed with sat'd NaCl and dried. The solution is filtered and the filtrate evaporated in vacuo yielding the desired product as its hydrochloride salt.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[N:4]1[CH3:13].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C@@H:3]1[CH2:8][N:7]2[CH2:9][CH2:10][CH2:11][C@H:6]2[C:5](=[O:12])[N:4]1[CH3:13])(=[O:24])=[O:23]
Reactant: CN1C(=O)[C@@H]2CCCN2C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1C(=O)[C@@H]2CCCN2C[C@H]1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 74.8 %

Procedure:
(3S,8aS)-3-(Hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one (505 mg, 2.74 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (0.8 mL, 5.75 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.45 mL, 5.81 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford [(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazin-3-yl]methyl methanesulfonate as an orange oil (538 mg, 2.05 mmol, 75% yield). 4-[(3,4-Dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-ol hydrochloride (469 mg, 1.20 mmol) was dissolved in dimethylformamide (1 mL) and potassium carbonate (828 mg, 6.00 mmol) was added followed by [(3S,8aS)-2-methyl-1-oxooctahydropyrrolo[1,2-a]pyrazin-3-yl]methyl methanesulfonate (538 mg, 2.05 mmol) in dimethylformamide (1 mL). The mixture was stirred at 70° C. for 34 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil which was purified by column chromatography (6-8% methanol in dichloromethane) to afford a yellow foam (300 mg, 0.577 mmol, 48% yield). The yellow foam (100 mg) was purified further by column chromatography (ethyl acetate-ethanol 1:1) to afford (3S,8aS)-3-({[4-[(3,4-dichloro-2-fluorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1 (2H)-one as a yellow solid (60 mg). 1H NMR (400 MHz, CDCl3): 8.71 (s, 1H), 8.52 (dd, 1H), 7.36-7.32 (m, 2H), 7.01 (s, 1H), 4.49 (dd, 1H), 4.34 (dd, 1H), 4.03 (s, 3H), 3.90-3.84 (m, 1H), 3.47 (t, 1H), 3.13 (s, 3H), 3.05 (dd, 1H), 2.95 (dd, 1H), 2.93-2.83 (m, 2H), 2.29-2.19 (m, 1H), 2.03-1.84 (m, 2H), 1.83-1.70 (m, 1H); MS (EI) for C24H24N5O3FCl2: 520 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)(=[O:13])=[O:12].N1CCCCC1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[C:20](\[C:17]2[CH:16]=[CH:15][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:19][CH:18]=2)/[C:21]([OH:23])=[O:22])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(/C(=C\c2cccc(Br)c2)C(=O)O)cc1
Temperature: 25 °C

Procedure:
Aryl Bromide AB1 was prepared by the following procedure. To a solution of 3-bromobenzaldehyde (12.9 g, 70 mmol) in toluene (100 mL) was added 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) and piperidine (2 mL). After overnight refluxing, the mixture was cooled down to r.t. To the slurry thus formed, toluene was added (10 mL). Filtration gave (E)-3-(3-Bromophenyl)-2-[4-(methylsulfonyl)phenyl]-2-propenoic acid as a white solid.