Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[F:15][C:16]([F:37])([F:36])[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1>C(O)C>[Br:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:33]2[CH2:34][CH2:35][N:30]([CH:27]3[CH2:26][CH2:25][N:24]([C:21]4[CH:20]=[CH:19][C:18]([O:17][C:16]([F:37])([F:15])[F:36])=[CH:23][CH:22]=4)[CH2:29][CH2:28]3)[CH2:31][CH2:32]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: FC(F)(F)Oc1ccc(N2CCC(N3CCNCC3)CC2)cc1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Solvent: CCO
Product: C[C@](O)(CN1CCN(C2CCN(c3ccc(OC(F)(F)F)cc3)CC2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Temperature: 50 °C
Reaction time: 8 h
Yield: 76.5 %

Procedure:
A mixture of (R)-2-bromo-4-nitro-1-(2-methyl-2-oxiranylmethyl)imidazole (485 mg, 1.75 mmol), 1-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazine (720 mg, 2.19 mmol) and ethanol (10 ml) was stirred at 50° C. for 8 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=20/1) to obtain (S)-1-(2-bromo-4-nitroimidazol-1-yl)-2-methyl-3-{4-[1-(4-trifluoromethoxyphenyl)piperidin-4-yl]piperazin-1-yl}propan-2-ol (792 mg, yield 77%) as a yellow amorphous form.
Reaction SMILES: Br[CH:2]([C:4]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)OCC(C)(C)CO1)C.[C:19](=O)([O-:21])[O-:20].[K+].[K+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:18][C:15]1[CH:14]=[CH:13][C:12]([CH:4]([CH3:2])[C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1
Reactant: CC(Br)C1(c2ccc(O)cc2)OCC(C)(C)CO1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C(=O)O)c1ccc(O)cc1
Temperature: 90 °C
Reaction time: 36 h
Yield: 30 %

Procedure:
A mixture of 2-(1'-bromoethyl)-5,5-dimethyl-2-(4'-hydroxyphenyl)-1,3-dioxane (3.15 g; 0.01 mole), potassium carbonate (6.8 g; 0.05 mole), tetrabutylammonium bromide (0.06 g; 0.0002 mole) in toluene (30 ml) is heated under stirring for 36 hours at 90° C. The mixture is then poured into a 1N hydrochloric acid solution (300 ml), the organic phase is separated and the aqueous phase is extracted again with toluene. The organic phases are combined, and the residue is hydrolyzed as in Example 1c to obtain 2-(4'-hydroxyphenyl)-propionic acid (0.49 g; 0.003 mole; yield of 30%). The characteristics of the product are identical to those given in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30]C)[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([NH:18][C:19](=[O:25])[C:20]([O:22]CC)=[O:21])=[CH:13][C:12]=2[CH3:26])=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[OH:30])[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([NH:18][C:19](=[O:25])[C:20]([OH:22])=[O:21])=[CH:13][C:12]=2[CH3:26])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(Cc3ccc(F)cc3)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Cc1ccc(O)c(Cc2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
102 mg (0.22 mmol) of ethyl ({4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylphenyl}amino)(oxo)acetate (Example 3) in 5 ml of dichloromethane at −78° C. under argon are treated slowly with 65 mg (0.25 mmol) of BBr3. The reaction mixture is stirred overnight while reaching room temperature. It is again cooled to −78° C. and a further 65 mg (0.25 mmol) of BBr3 is added. The mixture is stirred at room temperature for 2 hours. Pouring into ice-water, stirring for 2 hours, extraction with dichloromethane and ethyl acetate and drying over sodium sulphate are followed by concentration in a rotary evaporator. The residue is stirred with ether and the solid is filtered off with suction. 51 mg (48%) of ({4-[3-(4-fluorobenzyl)-4-hydroxy-benzyl]-3,5-dimethylphenyl}amino)(oxo)acetic acid are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([O:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18]C)=[O:17])[CH:9]=2)[CH2:4][CH2:3]1.CO.[OH-].[Na+].O>C(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:8]([O:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([OH:18])=[O:17])[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCCCCOc1cc2c(cc1OCc1cccc(C(=O)OC)c1)C(=O)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCCOc1cc2c(cc1OCc1cccc(C(=O)O)c1)C(=O)CC2
Yield: 68 %

Procedure:
A mixture of the compound obtained in Example 3 (2.3 g; 6.01 mmol), methanol (330 ml), sodium hydroxide (0.96 g; 24 mmol) and water (24 ml) is refluxed for 3 hours. The medium is concentrated to dryness. The residue is taken up in water. The basic aqueous phase is washed with ethyl ether and then acidified with 1N HCl. The cream-coloured precipitate formed is dissolved in methylene chloride. The organic phase is washed with water, dried over sodium sulfate and concentrated (1.5 g; 68% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=5)[CH2:22][CH2:21]4)[C:15](=[O:33])[CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:34]=1.[CH3:35][NH:36][CH3:37]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH:20]4[CH2:21][CH2:22][N:23]([C:26]5[CH:31]=[CH:30][N:29]=[C:28]([N:36]([CH3:37])[CH3:35])[N:27]=5)[CH2:24][CH2:25]4)[C:15](=[O:33])[CH2:14]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:34]=1
Reactant: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CC1CCN(c2ccnc(Cl)n2)CC1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1nccc(N2CCC(CN3CCN(S(=O)(=O)c4cc5ccc(Cl)cc5s4)CC3=O)CC2)n1
Temperature: 80 °C

Procedure:
To a solution of 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one (17 mg, 0.031 mmole) in ethanol (1 mL) is added a 40% solution of dimethylamine (11 mg, 0.094 mmole). This mixture is heated at 80° C. in a sealed tube 16 h. The reaction is concentrated and lyophilized to provide 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[1-(2-dimethylamino-pyrimidin-4-yl)-piperidin-4-ylmethyl]-piperazin-2-one. 1H NMR (300 MHz, CDCl3) d 7.93-7.84 (m, 4H), 7.48 (dd, 1H), 5.84 (d, 1H), 4.32 (d, 2H), 3.87 (s, 2H), 3.47 (s, 4H), 3.26 (d, 2H), 3.14 (s, 6H), 1.99-1.90 (m, 1H), 1.62 (d, 2H), 1.27-1.17 (m, 2H); MS (Ion spray) 549 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])=[CH:4][C:3]=1[O:22][CH3:23].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH3:23][O:22][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[C:12]([O:19][CH3:20])[C:11]=2[CH3:21])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:1][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(=O)c2c(C)c(OC)c3ccccn23)ccc1N
Product: CCOC(=O)CNc1ccc(C(=O)c2c(C)c(OC)c3ccccn23)cc1OC

Procedure:
This compound was obtained according to the same procedure as that described in Example 192, by alkylating (4-amino-3-methoxyphenyl)(1-methoxy-2-methylindolizin-3-yl)methanone, a compound of Example 94, with ethyl bromoacetate. A yellow powder is obtained.
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([CH:9]([CH3:13])[C:10](Cl)=[O:11])=[C:7]([F:14])[C:6]([F:15])=[C:5]([F:16])[C:4]=1[F:17]>O>[F:2][C:3]1[C:8]([CH:9]([CH3:13])[C:10]([NH2:1])=[O:11])=[C:7]([F:14])[C:6]([F:15])=[C:5]([F:16])[C:4]=1[F:17]
Reactant: CC(C(=O)Cl)c1c(F)c(F)c(F)c(F)c1F
Reactant: N
Solvent: O
Product: CC(C(N)=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled 10 ml of concentrated aqueous ammonia, was added dropwise 2.5 g of (-)-2-(pentafluorophenyl)-propanoyl chloride obtained in Example 5. After stirring for 30 minutes at room temperature, the reaction mixture was diluted with water, extracted with ethyl acetate and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the subsequent recrystallization from a hexane-ether mixed solvent gave 1.92 g of (-)-2-(pentafluorophenyl)propaneamide as colorless needles having the aforementioned physical properties.
Reaction SMILES: [CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1>CN(C)C=O>[CH2:1]([C:5]1[S:21][C:8]2[N:9]=[C:10]3[CH:17]=[CH:16][C:15]([C:18]([NH:35][C:36]4[NH:40][N:39]=[N:38][N:37]=4)=[O:20])=[CH:14][N:11]3[C:12](=[O:13])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1
Temperature: 105 °C

Procedure:
1.6 g (0.0053 mol) of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid (Example 4) and 1.75 g (0.0108 mol) of 1,1'carbonyldiimidazole (Aldrich Chemical Company) in 50 ml of dimethylformamide are stirred under a nitrogen atmosphere at 105° C. for seventy minutes. The mixture is allowed to stand at room temperature for thirty minutes and then 0.545 g (0.00529 mol) of 5-aminotetrazole monohydrate (Aldrich Chemical Company) is added and the mixture heated at 105° C. for one hundred minutes. The solvent is evaporated and the residue is dissolved in dimethylformamide and filtered. The filtrate is cooled and 1.1 g of 2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]-pyrimidine-7-carboxamide is collected; mp 290° (dec).
Reaction SMILES: C([Li])CCC.[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20](COCCO)=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:32]([S:34]SCC)[CH3:33].C([O-])(=O)C.[NH4+]>C1COCC1.CO.O>[C:6]([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C@H:15]([CH2:16][C:17]3[C:22]2=[N:21][C:20]([S:34][CH2:32][CH3:33])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CCSSCC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Agent: CC(=O)[O-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCSc1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 37.6 %

Procedure:
THF (5 mL) was cooled to −78° C. under an argon atmosphere. n-Butyl lithium (1.6 M in hexanes, 0.5 mL, 0.8 mmol) was added and the mixture was stirred at −78° C. for 5 min. A mixture of (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 5, intermediate b) (0.2 g, 0.54 mmol) in THF (5 mL) was added dropwise, maintaining the temperature below −70° C. The resultant dark red solution was stirred at −78° C. for 30 min and ethyl disulfide (0.13 mL, 1.08 mmol) was added. The mixture was stirred at −78° C. for 2 h and left to warm to room temperature over 2 h. Water (1 mL) was added and the mixture was poured onto an isolute HM-N SPE cartridge and eluted with ethyl acetate (10 mL). The eluant was evaporated under reduced pressure and the crude material was purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.071 g, 53% yield) as a pale yellow oil: m/z 350.14 (MH+); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 220 nm XTERRA 2.0 ml/min) 6.21 min. (4R,9aR)-6-Ethylsulfanyl-4-methyl-1,2,3,4,9,9a-hexahydro-2-4a,5-triaza-fluorene
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])[CH:16]=[N:17][CH:18]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: COc1cncc(Br)c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cncc(N2CCN(c3cnccc3C)C2=O)c1
Yield: 9.6 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 3-bromo-5-methoxy-pyridine (159.24 mg, 0.847 mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform), followed by preparative HPLC afforded 23 mg of the product (9.55% yield).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][N:11]3[CH:14]=[N:15][CH:16]=[C:10]3[CH:9]=2)[CH2:4][CH2:3]1.Br[C:18]1C=CN=C(CNC(=O)C)C=1.BrC1C=CN=C(CNC=O)C=1>>[ClH:1].[CH3:18][C:14]1[N:11]2[CH:12]=[CH:13][C:8]([CH:5]3[CH2:4][CH2:3][NH:2][CH2:7][CH2:6]3)=[CH:9][C:10]2=[CH:16][N:15]=1
Reactant: CC(=O)NCc1cc(Br)ccn1
Reactant: c1cn2cncc2cc1C1CCNCC1
Agent: Cl
Agent: O=CNCc1cc(Br)ccn1
Product: Cc1ncc2cc(C3CCNCC3)ccn12

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 39.5, except N-((4-bromopyridin-2-yl)methyl)acetamide (compound 67.1) was used in place of N-((4-bromopyridin-2-yl)methyl)formamide (compound 39.2).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]([S:28]([CH3:31])(=[O:30])=[O:29])[C:5]1[C:6]([CH:25]2[CH2:27][CH2:26]2)=[CH:7][C:8]2[C:12]([CH:13]=1)=[N:11][N:10]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]=2[C:21]([NH:23][CH3:24])=[O:22].Cl.[NH:33]1[CH2:36][CH:35]([OH:37])[CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:10]2[C:9]([C:21]([NH:23][CH3:24])=[O:22])=[C:8]3[C:12]([CH:13]=[C:5]([N:4]([CH2:3][CH2:2][N:33]4[CH2:36][CH:35]([OH:37])[CH2:34]4)[S:28]([CH3:31])(=[O:30])=[O:29])[C:6]([CH:25]4[CH2:27][CH2:26]4)=[CH:7]3)=[N:11]2)=[CH:15][CH:16]=1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCBr)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCN3CC(O)C3)S(C)(=O)=O)cc2nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 6-[2-bromoethyl(methylsulfonyl)amino]-2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-indazole-3-carboxamide (5 mg, 0.01 mmol) in MeCN (500 uL) was added azetidin-3-ol hydrochloride (6.6 mg, 0.06 mmol) followed by potassium carbonate (6 mg). The resultant suspension was heated at 65 deg C. in a sealed vial and after 3 days, cooled to RT then filtered through a cotton wool plug. The residue was washed with MeCN (2 mL) and the volatiles removed in vacuo. The residual colourless oil was purified by preparative HPLC/MS (MeCN/0.1% formic acid in water (v/v)-gradient elution) to give Compound (22) as a white amorphous solid (4.5 mg, 91%). 1H NMR (400 MHz, CD3CN) δ 7.90 (s, 1H), 7.63-7.53 (m, 4H), 7.42 (s, 1H), 7.03 (br s, 1H), 4.67-4.40 (m, 2H), 4.17 (br s, 2H), 3.96 (br s, 2H), 3.80 (br s, 1H), 3.38 (br s, J=41.2 Hz, 2H), 3.16 (s, 3H), 2.91 (d, J=4.8 Hz, 3H), 2.34-2.33 (m, 1H), 1.18-1.01 (m, 3H), 0.68-0.58 (m, 1H). ESI-MS m/z calculated for [M+H]+: 518.16. found: 518.10.
Reaction SMILES: C([O:5][C:6](=[O:20])[NH:7][CH:8]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)[CH2:9]O)(C)(C)C.[H-].[Na+]>C1COCC1>[F:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[F:18])[CH2:11][CH:8]1[CH2:9][O:20][C:6](=[O:5])[NH:7]1
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(F)c(F)c2)CO1
Reaction time: 3 h
Yield: 37.5 %

Procedure:
A solution of (+)-[1-(3,4-difluorobenzyl)-2-hydroxy-ethyl]-carbamic acid-tert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL) was added via a dropping funnel to a stirring suspension of 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with water (10 mL). The biphasic mixture was extracted with Et2O (50 mL), washed with brine, filtered and the solvent was removed in vacuo. The resulting gummy residue was purified by column chromatography (Rf=0.25, 3:2 hexane-EtOAc), to give the desired product as a white solid (0.320 g, 76%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CCCCC[Mg]Br
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 27.91 g (99.5 mmol) of 4-t-butyldimethylsilyloxymethyl-2-methoxybenzaldehyde (prepared as described in Preparation 40) in 100 ml of tetrahydrofuran was added dropwise to 100 ml of an ice-cooled 1.62 M solution of pentylmagnesium bromide in tetrahydrofuran over a period of 30 minutes, and then the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then mixed with a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with a mixture of ethyl acetate and hexane. The extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, to give 30.67 g (yield 87%) of the title compound as an oily substance.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]([NH:17][C@H:18]([CH2:24][F:25])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-]>CO.O>[CH2:7]([O:14][C:15]([NH:17][C@H:18]([CH2:24][F:25])[CH2:19][CH2:20][C:21]([O:23][CH3:1])=[O:22])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Agent: [Cs+]
Solvent: O
Solvent: CO
Product: COC(=O)CC[C@@H](CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 20% aqueous solution of cesium carbonate was slowly added to a mixture of 14.2 g of 10 in 230 ml of methanol and 23 ml of water, until the mixture was neutral (about 50 ml of the carbonate solution). The solvent was evaporated under reduced pressure. The residue was placed in 50 ml of dimethylformamide and stripped twice. The residue was placed in 150 ml of dimethylformamide and 50 ml of methyl iodide was added to the mixture, which then was stirred overnight at room temperature. The mixture was filtered, and a large volume of methylene chloride was added to the filtrate. The filtrate was washed with a large volume of water, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane, the mixture was filtered, and the solvent was evaporated from the filtrate to give 13, as a tan solid, m.p.: 46°-48° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].C([NH2:22])C1C=CC=CC=1>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Product: Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in schemes 16 and 18) can be treated with a benzylic amine, such as benzylamine, to displace the chloro moiety. Hydrogenation under standard conditions can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the desired 2,5-diamino-benzenesulfonamide intermediate.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][CH:5]([C:8]2[S:9][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](O)[C:15]=3[N:16]=2)[CH2:4][CH2:3]1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:29])=O>CN(C=O)C>[Cl:29][C:14]1[C:15]2[N:16]=[C:8]([CH:5]3[CH2:6][CH2:7][C:2]([CH3:19])([CH3:1])[CH2:3][CH2:4]3)[S:9][C:10]=2[N:11]=[C:12]([CH3:18])[N:13]=1
Reactant: Cc1nc(O)c2nc(C3CCC(C)(C)CC3)sc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c2nc(C3CCC(C)(C)CC3)sc2n1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidin-7-ol (16.2 g) and toluene (160 mL) were added DMF (10 mL) and phosphorous oxychloride (11 mL), followed by stirring at 95° C. for 30 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added chloroform, and the mixture was neutralized with a 1 M aqueous NaOH solution in an ice bath and extracted with chloroform. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain 7-chloro-2-(4,4-dimethylcyclohexyl)-5-methyl[1,3]thiazolo[5,4-d]pyrimidine (13.2 g).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH:8]=[N:9][CH2:10][CH2:11][C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[C:16]3[CH:15]=[CH:14][S:13][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=NCCc2cccs2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2NCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 85 %

Procedure:
The above (4-nitrobenzylidene)-(2-thiophen-2-yl-ethyl)-amine (1 g, 3.8 mmol) was added trifluoroacetic acid (100 ml) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 72 hours, then evaporated in vacuo. Crystallisation from a mixture of diethyl ether and dichloromethane afforded 1.2 g (85%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([N+:30]([O-])=O)[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.O.O.[Sn](Cl)Cl.C(=O)(OC(C)(C)C)OC(C)(C)C.[OH-].[Na+]>C(OCC)(=O)C>[NH2:30][C:28]1[CH:27]=[C:4]([CH:3]=[C:2]([Br:1])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc([N+](=O)[O-])c2)(c2ccccc2)CC1
Agent: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(N)cc(Br)c2)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-((3-bromo-5-nitrobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (1.36 g, 2.69 mmol) and tin (II) chloride dihydrate (6.48 g, 28.7 mmol) were combined in ethyl acetate (20 mL) and heated at reflux for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate and concentrated. The crude product was dissolved in tetrahydrofuran (10 mL), cooled to 0° C. and treated with di-tert-butyl carbonate (0.59 g, 2.69 mmol) and 10 N sodium hydroxide (0.65 mL). The reaction was allowed to warm to room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (2×), dried over sodium sulfate and concentrated. Column chromatography on silica gel (30% ethyl acetate/hexanes) gave 0.25 g (19%). LC/MS (HPLC method 3): tR=2.99 min, 477.05 (MH)+.