Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:4][CH:3]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(Br)cc1
Yield: 87.4 %

Procedure:
4-bromophenol (10.46 g, 60.5 mmol), 1-bromooctane (15.43 g, 79.9 mmol) and potassiumcarbonate (90 g, 0.65 mol) in N,N-dimethylformamide and was heated to 90° C. for 4 h and then the potassiumcarbonate was filtered off The reaction mixture was quenched with water and extracted three times with ether. The ether was then washed three times with 1M hydrochloric acid (HCl), one time with water, evaporated, and purified by distillation to obtain 1-bromo-4-(octyloxy)benzene (15.1 g, 52.9 mmol) as a colourless oil.
Reaction SMILES: BrC1C2C1CNC1C=CC=CC=12.BrC1C2C3CC3C(=O)NC=2C=CC=1.[Br:26][C:27]1[C:32]2[O:33][CH2:34][C:35](=O)[NH:36][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[Br:26][C:27]1[C:32]2[O:33][CH2:34][CH2:35][NH:36][C:31]=2[CH:30]=[CH:29][CH:28]=1
Reactant: O=C1COc2c(Br)cccc2N1
Agent: BrC1C2CNc3ccccc3C12
Agent: O=C1Nc2cccc(Br)c2C2CC12
Product: Brc1cccc2c1OCCN2

Procedure:
The title compound was prepared using a procedure analogous to bromo-1a,2,3,7b-tetrahydro-1H-cyclopropa[c]quinoline except that 7-bromo-3,7b-dihydro-1H-cyclopropa[c]quinolin-2(1aH)-one was replaced with 8-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one. LCMS, [M+H]+=214.0. 1H NMR (400 MHz, CDCl3) δ 6.90 (dd, J=7.9, 1.5 Hz, 1H), 6.63 (t, J=7.9 Hz, 1H), 6.53 (dd, J=7.9, 1.5 Hz, 1H), 4.33-4.39 (m, 2H), 3.42-3.48 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:28]2[CH:33]=[C:32]([C:34]3[O:39]C(C)(C)[O:37][C:36](=O)[CH:35]=3)[CH:31]=[CH:30][N:29]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:36](=[O:37])[CH2:35][C:34]([C:32]1[CH:31]=[CH:30][N:29]=[C:28]([N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:33]=1)=[O:39])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2ccnc(-n3ccnc3)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1ccnc(-n2ccnc2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J14) according to the general procedure K. Obtained as a brown solid (361 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[O:23][C:24]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)=[CH:34][CH:33]=4)=[C:25]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]=23)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:41]1([CH2:40][CH2:39][O:38][C:35]2[CH:36]=[CH:37][C:32]([C:24]3[O:23][C:19]4[N:20]=[CH:21][CH:22]=[C:17]([NH:16][CH2:15][CH2:14][N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[C:18]=4[C:25]=3[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:33][CH:34]=2)[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ccnc3oc(-c4ccc(OCCN5CCOCC5)cc4)c(-c4ccccc4)c23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2c(-c3ccc(OCCN4CCOCC4)cc3)oc3nccc(NCCN4CCNCC4)c23)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-{2-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-3-phenyl-furo[2,3-b]pyridin-4-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester 10d (0.062 g, 0.099 mmol) in dichloromethane (1.0 mL) was cooled to 0° C. Trifluoroacetic acid (0.5 mL) was added and the solution stirred under a nitrogen atmosphere at 0° C. for 15 min and then at room temperature for 2.5 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-(4-((2-(4-morpholinyl)ethyl)oxy)phenyl)-3-phenyl-N-(2-(1-piperazinyl)ethyl)furo[2,3-b]pyridin-4-amine 10e as an off-white solid. MS (MH+) 528.3; Calculated 527 for C31H37N5O3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([N+:15]#[C-:16])=[C:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])[CH3:2].C(N(CC)CC)C.[CH2:25]([NH2:29])[CH:26]([CH3:28])[CH3:27]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:5]1[N:15]=[CH:16][N:29]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])=[O:17])[CH3:2]
Reactant: [C-]#[N+]C(C(=O)OCC)=C(Br)c1ccccc1Br
Reactant: CC(C)CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(CC(C)C)c1-c1ccccc1Br
Yield: 71 %

Procedure:
A 0.5 M solution of 3-bromo-3-(2-bromophenyl)-2-isocyano-acrylic acid ethyl ester (2.55 g; 7.11 mM) and triethylamine (990 μl; 7.11 mM) in dimethylformamide (DMF) is added drop by drop at room temperature with isobutylamine (850 μl; 8.53 mM). The reaction mixture is kept at room temperature until complete reaction, then is quenched with a NaHCO3 saturated solution, extracted with ethyl acetate, washed with water, dried over Na2SO4, and evaporated under reduced pressure. The crude is purified by flash chromatography, eluting with ethyl acetate, to obtain 1.77 g of 5-(2-bromophenyl)-1-isobutyl-1H-imidazole-4-carboxylic acid ethyl ester. (Yield: 71%).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34].C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[CH2:13][C:12]2([CH3:35])[CH3:34]
Reactant: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)O)cc(Cl)cc21
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(c2cccc(N3CCOCC3)c2)Nc2c(C(=O)NS(C)(=O)=O)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 8 %

Procedure:
To a suspension of 60% sodium hydride (361 mg, 9 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (865 mg, 9.1 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A62. A solution of 6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (520 mg, 1.3 mmol) and 1,1′-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B62. Solution B62 was added to Solution A62 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-chloro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (50 mg, 8%) as a white solid: MS (ESI) M+1=478.2.
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:23]=[C:24]([F:26])[CH:25]=1>>[F:26][C:24]1[CH:23]=[C:22]([C:27]2([OH:33])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:21]=[C:20]([F:19])[C:25]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: OC1(c2cc(F)cc(F)c2)CCOCC1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC1(C)OB(c2c(F)cc(C3(O)CCOCC3)cc2F)OC1(C)C
Yield: 97 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 equiv.), butyllithium (2.4 equiv.) and 4-(3,5-difluorophenyl)tetrahydro-2H-pyran-4-ol (1.0 equiv.) to give 4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol in 97% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.32-1.42 (m, 12H), 1.56-1.65 (m, 2H), 2.11 (d, J=3.13 Hz, 2H), 3.86-3.92 (m, 4H), 6.99 (d, J=9.00 Hz, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.[OH-].[Na+]>C1COCC1.CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)CSc1ccc2nnc(-c3cccs3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CSc1ccc2nnc(-c3cccs3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetate (50 mg, 0.156 mmol) dissolved in a 2/1 mixture of THF and MeOH was added 100 uL of 2N NaOH, and the whole was stirred at room temperature for 3 h. The reaction mixture was then evaporated to dryness, the residue dissolved in water (5 mL), and the solution acidified with 6M HCl. The resulting precipitate was filtered, washed twice with cold water, and dried to give acid 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thio)acetic acid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][Cl:26])=[CH:23][CH:22]=1>CCO>[ClH:26].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][S:18][C:9]2[NH:8][C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C@H:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=2)=[CH:23][CH:22]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: COc1ccc(CCl)cc1
Solvent: CCO
Product: COc1ccc(CSC2=N[C@@H](c3ccccc3)[C@@H](c3ccccc3)N2)cc1
Product: Cl
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 4-methoxybenzyl chloride (0.213 mL, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 167 mg of the product 223. 1H NMR (DMSO-d6) δ 11.24 (s, 2H), 7.50 (d, 2H), 7.20-6.90 (m, 8H), 6.90-6.65 (m, 4H), 5.78 (s, 2H), 4.78 (s, 2H), 3.78 (s, 3H); MS: m/z 375 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][C:24]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=1)([CH3:26])[CH3:25]>>[C:24]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH:33][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:21])[N:31]=1)([CH3:26])([CH3:23])[CH3:25]
Reactant: CC(C)(C)c1nc(CN)cs1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Product: CC(C)(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)cs1

Procedure:
The title compound was synthesized in analogy to Example 41 using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAS Registry No. 937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 99.1%, 485.2 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([NH2:17])=[S:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrBr.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[NH2:17][C:15]1[S:16][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]=2[N:14]=1
Reactant: NC(=S)Nc1ccccc1Oc1ccccc1
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc2c(Oc3ccccc3)cccc2s1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a mixture of 1-(2-phenoxyphenyl)thiourea (53.4 g) in chloroform (100 ml) was added dropwise a solution of bromine (35.0 g) in chloroform (50 ml) with stirring under ice-cooling during 40 minutes. After refluxing for 1 hour and 40 minutes, the mixture was cooled to ambient temperature. To the resultant mixture was added water and then the mixture was alkalified with 5% sodium hydroxide aqueous solution. The chloroform layer was washed with water, dried over magnesium sulfate, concentrated under reduced pressure to give crystals, which were recrystallized twice from isopropyl alcohol to give 2-amino-4-phenoxybenzothiazole (25.8 g). mp: 135°-137° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([O:23]CC)=[O:22])=[CH:13][N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].Cl>O1CCCC1.CO.O.[OH-].[Na+]>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[C:15]([NH:17][CH2:18][CH2:19][CH3:20])[C:14]([C:21]([OH:23])=[O:22])=[CH:13][N:12]=2)=[CH:8][CH:9]=1)(=[O:3])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Temperature: 60 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
To a solution of ethyl 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C1, 8.0 g) in tetrahydrofuran (240 mL) and methanol (240 mL), water (40 mL) and 5.0 mol/L aqueous sodium hydroxide (48 mL) were added at room temperature, and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled on ice, then 12 mol/L aqueous hydrochloric acid was added to the mixture until pH of the mixture became 2, and the reaction mixture was poured into ice water (2000 mL). The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2, 4.0 g) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])[CH:5]=[CH:6][CH:7]=1.[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:32][CH2:31][CH:27]([C:28]([Cl:30])=[O:29])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[ClH:30].[N:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:25][CH2:26][CH:27]([C:28]([NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:17])=[O:29])[CH2:31][CH2:32]2)=[CH:20][CH:19]=1
Reactant: Nc1ccccc1C(=O)Nc1cccc(F)c1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: Cl
Product: O=C(Nc1cccc(F)c1)c1ccccc1NC(=O)C1CCN(c2ccncc2)CC1
Yield: 68 %

Procedure:
Using the procedure described in Example 138, N-(3-fluorophenyl)-2-aminobenzamide (1.3 mmol) and N-(4-pyridyl)isonipecotoyl chloride (2.6 mmol), purifying with RPHPLC Method D, yielded 402 mg (68%) of the title compound.
Reaction SMILES: [C:1]1([CH:7]([N:19]2[CH2:24][CH2:23][S:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>C(OCC)(=O)C>[Cl-:25].[O:28]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N:19]1[CH2:24][CH2:23][S:22][CH2:21][CH2:20]1)[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCSCC1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCSCC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
(R)-quinuclidin-3-yl 2-phenyl-2-thiomorpholinoacetate (68 mg, 0.20 mmol) was dissolved in ethyl acetate (2 ml) and 2-chloro-1-phenylethanone (33.4 mg, 0.22 mmol) was added. The solution was stirred at room temperature for two days. The solvent was evaporated and the residue was triturated with Et2O. The suspension was filtered on a buckner funnel to obtain (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-thiomorpholinoacetoxy)-1-azoniabicyclo[2.2.2]octane chloride (89 mg, 0.178 mmol, 91% yield) as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]([OH:12])[CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[S:27](Cl)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:34][C:33]1[CH:35]=[CH:36][C:30]([S:27]([O:12][CH:9]([CH2:10][CH3:11])[C@@H:8]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:29])=[O:28])=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(OS(=O)(=O)c1ccc(C)cc1)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-tert-butyl 1-cyclohexyl-3-hydroxypentan-2-ylcarbamate (1.067 g, 3.74 mmol), catalytic amount of DMAP, and pyridine (0.651 g, 8.24 mmol) at 0° C. was added TsCl (0.856 g, 4.49 mmol) in CH2Cl2 (4 mL) over 2 min. The resulting solution was stirred at rt overnight. The reaction mixture was diluted with EtoAc, washed with 1 M HCl, sat. aq. NaHCO3, brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by on silica gel chromatography to give (S)-2-(tert-butoxycarbonylamino)-1-cyclohexylpentan-3-yl 4-methylbenzenesulfonate as a white solid. MS ESI +ve m/z 462 (M+Na).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]([N:5]=[C:6]1[N-:10][N:9]=[C:8]([S:11][CH3:12])[S:7]1)=[O:4].[Na].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(#N)C>[CH2:19]([O:18][C:16]([N:10]1[N:9]=[C:8]([S:11][CH3:12])[S:7][C:6]1=[N:5][C:3](=[O:4])[N:2]([CH3:13])[CH3:1])=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: CSc1n[n-]c(=NC(=O)N(C)C)s1
Agent: [Na]
Solvent: CC#N
Product: CCOC(=O)n1nc(SC)sc1=NC(=O)N(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
80.5 g of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazol-3-id, sodium salt, were suspended in 300 ml of acetonitrile and treated dropwise with stirring with 36.5 g of ethyl chloroformate at room temperature. The mixture was further stirred for 2 hours, treated with ice water, the precipitated substance separated by suction filtration, and recrystallized from acetonitrile. There is obtained 84.5 g (86.9% of theory) of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid ethyl ester of m. pt. 129° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([OH:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:26])=[CH:7][C:5]=2[N:6]=1.Cl(O)(=O)(=O)=O.[C:32](O[C@@H](C1C(C)=CC2N=C(Br)SC=2C=1OS(C(F)(F)F)(=O)=O)C(OCC)=O)([CH3:35])([CH3:34])[CH3:33]>C(OC(C)(C)C)(=O)C>[C:32]([O:25][C@@H:19]([C:9]1[C:8]([CH3:26])=[CH:7][C:5]2[N:6]=[C:2]([Cl:1])[S:3][C:4]=2[C:10]=1[O:11][S:12]([C:15]([F:18])([F:16])[F:17])(=[O:14])=[O:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Reactant: CCOC(=O)[C@@H](O)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Cl)sc2c1OS(=O)(=O)C(F)(F)F
Reaction time: 1.5 h

Procedure:
To a solution of (S)-ethyl 2-(2-chloro-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)-2-hydroxyacetate (0.5691 g, 1.31 mmol) in tert-butyl acetate (65 mL) was added 70% perchloric acid (65 μL, 1.57 mmol). Reaction mixture was stirred for 1.5 h and quenched with solid sodium bicarbonate. Saturated sodium bicarbonate solution was carefully added until basic and mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 15% EtOAc/Hex) to give product contaminated with (S)-ethyl 2-tert-butoxy-2-(2-bromo-5-methyl-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate. 1H NMR (400 MHz, CDCl3): δ 7.78 (s, 1H), 5.59 (s, 1H), 4.4-4.1 (m, 2H), 2.55 (s, 3H), 1.20 (s, 9H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[C:8]([C:15]1[C:16]([Cl:20])=[N:17][S:18][N:19]=1)=[C:9]([Cl:14])[CH2:10]2)=O)C.[Cl-].[Cl-].[Cl-].[Al+3].O>C1(C)C=CC=CC=1>[Cl:14][C:9]1[CH2:10][CH:11]2[NH:6][CH:7]([CH2:13][CH2:12]2)[C:8]=1[C:15]1[C:16]([Cl:20])=[N:17][S:18][N:19]=1
Reactant: CCOC(=O)N1C2CCC1C(c1nsnc1Cl)=C(Cl)C2
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: ClC1=C(c2nsnc2Cl)C2CCC(C1)N2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 8-ethoxycarbonyl-3-chloro-2-(3-chloro-1,2,5-thiadiazol-4-yl)-8-azabicyclo[3.2.1]oct-2-ene (1.7 g, 5 mmol) (PCT/DK91/00236) in dry toluene (50 ml) was added aluminium trichloride (2.6 g, 20 mmol). The reaction mixture was heated to 80° C. and kept at this temperature for 10 min. After cooling water was carefully added to the reaction mixture. The water solution was extracted with methylene chloride (2×50 ml), then made basic with 4N sodiumhydroxide solution. The alkaline solution was extracted with diethylether (3×100 ml). The organic extracts from the basic extractions were dried over magnesium sulfate and evaporated. The residue was crystallized as the oxalate salt from acetone in 1.60 g yield.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[C:11](Cl)(=[O:15])C(Cl)=O.[NH3:17].C(Cl)Cl>C1COCC1>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:17]=[C:11]=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C=NC(=O)c1ccc(I)cc1

Procedure:
The title compound was prepared according to the procedures described in step-2 and step-3 of Intermediate-26 by using 4-iodo benzoic acid (2.0 g), oxalyl chloride (1.0 ml), ammonia gas, DCM (20 mL), THF (20 mL) to afford 1.5 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 7.17 (br s, 1H), 7.64 (d, 2H), 8.01 (s, 2H); MS (m/z): 461.14 (M+H)+.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)=[CH:25][CH:24]=[CH:23][C:14]=1[CH2:15][O:16]C1CCCCO1.[B:37](OC(C)C)(OC(C)C)[O:38]C(C)C.Cl>C1COCC1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][O:27][C:26]2[C:13]3[B:37]([OH:38])[O:16][CH2:15][C:14]=3[CH:23]=[CH:24][CH:25]=2)=[CH:30][CH:31]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(COc2cccc(COC3CCCCO3)c2Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(COc2cccc3c2B(O)OC3)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2.5 M n-BuLi in hexane (1.53 mL, 3.83 mmol) was added dropwise to a solution of 2-[2-bromo-3-(4-methoxy-benzyloxy)-benzyloxy]-tetrahydro-pyran (1.3 g, 3.2 mmol) in THF (14 mL) under N2 at −78° C. (bath temp). The mixture was stirred at −78° C. (bath temp) for 2 h then triisopropyl borate (0.90 mL, 3.8 mmol) was added slowly and stirred at −78° C. (bath temp) for 4 h. The mixture was allowed to warm up to 0° C. (bath temp) and then acidified with 3 M HCl to pH 5. The mixture was stirred for 3 h and the resulting precipitate was isolated by filtration and washed with 1:9 CH2Cl2/Et2O to give A25 as a yellow solid: yield 0.10 g (12%).