Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([OH:14])=[C:7]([OH:15])[CH:6]=1)=O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([NH2:25])=[S:24])[CH:17]=1>C(O)CCC>[BrH:1].[N+:11]([C:9]1[CH:10]=[C:5]([C:3]2[N:25]=[C:23]([NH:22][C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[S:24][CH:2]=2)[CH:6]=[C:7]([OH:15])[C:8]=1[OH:14])([O-:13])=[O:12]
Reactant: NC(=S)Nc1cccnc1
Reactant: O=C(CBr)c1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: CCCCO
Product: Br
Product: O=[N+]([O-])c1cc(-c2csc(Nc3cccnc3)n2)cc(O)c1O
Temperature: 25 °C

Procedure:
A suspension of 7.32 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is treated with 4.06 g of 1-(3-pyridinyl)-2-thiourea in 100 ml of n-butanol and heated to boiling under reflux for 3 hours. After cooling to room temperature the crystals are filtered under suction and recrystallized from n-butanol. There is obtained 3-nitro-5-[2-(3-pyridylamino)-4-thiazolyl]pyrocatechol hydrobromide of m.p. >300°.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[NH2:7][CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:12]=[CH:11][C:10]1=2.[BH4-].[Na+]>CO>[CH3:4][CH:3]([CH3:5])[CH2:2][CH2:1][NH:7][CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([O:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)CC=O
Reactant: NCC1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCC1CCCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.9 %

Procedure:
Add isovaleraldehyde (64.5 mg, 0.750 mmol) to a solution of 6-(5-aminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (intermediate 21, 148 mg, 0.500 mmol) dissolved in MeOH (5 mL) and stir at ambient temperature for 1.5 hours before adding NaBH4 (38 mg, 1.00 mmol). After stirring for an additional two hours, concentrate the reaction mixture and redissolved in EtOAc. Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain 123 mg of the title compound as a white foam.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Si]([CH:19]=[N+:20]=[N-:21])(C)(C)C>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:13])[CH:19]=[N+:20]=[N-:21])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(Cl)c1ccc(Br)c2ccccc12
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)c1ccc(Br)c2ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-Bromo-naphthalene-1-carbonyl chloride (13.8 g) was dissolved in dichloromethane (130 mL) and cooled to 0° C. TMS diazomethane solution (40 mL, 2 M in DCM) was added, and ice bath was removed. Reaction mixture was stirred for 18 hours and evaporated under vacuum, giving 1-(4-bromonaphthalen-1-yl)-2-diazoethanone (13.8 g, crude) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([CH3:21])=[C:4]([CH3:22])[N:3]=1.[H][H]>[Pt].C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]([CH3:21])=[C:4]([CH3:22])[N:3]=1
Reactant: [H][H]
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOc2ccccc2)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)c(N)c(NCCOc2ccccc2)c1C

Procedure:
Toluene (150 ml), 5% platinum on carbon (5.0 g), and 2-chloro-5,6-dimethyl-3-nitro-N-(2-phenoxyethyl)pyridin-4-amine (3.32 g) from Part B of Example 1 were placed in a Parr hydrogenation flask at a hydrogen pressure of 345 kPa for 4 hours with shaking. HPLC analysis indicated that the reaction was complete. The reaction mixture was filtered through a fluted filter paper and then through a folded No. 2 Whatman filter. The solvent was removed from the filtrate under reduced pressure and the resulting brown oil was used in the next step.
Reaction SMILES: [Br-].[NH2:2][C:3]1[N:4]([CH2:20][C:21](=[O:27])[C:22]2[S:26][CH:25]=[CH:24][CH:23]=2)[C:5]2[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=2[N+:7]=1[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.[C:29](OC(=O)C)(=O)[CH3:30]>>[CH3:29][C:30]1[N:2]=[C:3]2[N:4]([C:20]=1[C:21](=[O:27])[C:22]1[S:26][CH:25]=[CH:24][CH:23]=1)[C:5]1[CH:19]=[CH:18][CH:17]=[CH:16][C:6]=1[N:7]2[CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1n(CC(=O)c2cccs2)c2ccccc2[n+]1CCN1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: [Br-]
Solvent: O
Product: Cc1nc2n(CCN3CCCCC3)c3ccccc3n2c1C(=O)c1cccs1

Procedure:
The bromide obtained in Step A is heated at reflux in 15 ml of acetic anhydride until completely dissolved. Cool and pour into 50 ml of cold water. Neutralise with a solution of sodium carbonate and extract twice with 10 ml of chloroform each time. Combine the organic phases, pass over a column of alumina and evaporate. Recrystallise the residue from ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:3]=1[O:4][CH2:5][C:6]#N.[OH-:28].[Na+].Cl.[OH2:31]>C(O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[C:3]=1[O:4][CH2:5][C:6]([OH:31])=[O:28]
Reactant: O
Reactant: Cc1cccc(COCCCNc2ccc3ccccc3n2)c1OCC#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(COCCCNc2ccc3ccccc3n2)c1OCC(=O)O
Temperature: 60 °C

Procedure:
{2-Methyl-6-[3-(quinolin-2-ylamino)-propoxymethyl]-phenoxy}-acetonitrile (270 mg, 0.75 mmol) is dissolved in ethanol (6 mL). 10 N NaOH (750 μL, 7.5 mmol) is added, and the contents are heated to 60° C. for 4 hrs. The reaction is cooled to r.t. 2 N HCl (3.75 mL, 7.5 mmol) is added and the pH is adjusted to ˜4-6. The contents are poured into water (150 mL) and extracted with ethyl acetate (3×75 mL). The organic fractions were pooled and washed with brine (3×100 mL), dried over MgSO4, filtered and reduced under vacuum to dryness. The crude material was pure enough to test as is to give the title compound. 1H NMR (300 MHz, CDCl3) δ 11.04 (s (broad), 1H), 7.88 (d, 1H), 7.73 (d, 1H), 7.52-7.47 (m, 2H), 7.26-7.12 (m, 3H), 7.02-6.97 (m, 1H), 6.90 (d, 1H), 4.66 (s, 2H), 4.47 (s, 2H), 3.69 (t, 2H), 3.57-3.53 (m, 2H), 2.33 (s, 3H), 2.05 (quintet, 2H). MS (ESI) 381 (M+H)+.
Reaction SMILES: [C:1]([OH:18])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na].Cl.[NH2:21][OH:22]>C(O)(=O)C.O>[CH2:5]([C:4]1[CH:3]=[C:2]([C:1]([OH:18])=[O:17])[O:22][N:21]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: NO
Reactant: CCCCCCCCCCCCCCCC(=O)O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1cc(C(=O)O)on1
Temperature: 60 °C
Reaction time: 25 h

Procedure:
To a stirred, warm (55° C.) solution of hexadecanoic acid, 2,4-dioxo, ethyl ester, monosodium salt (15.50 g, 0.046 mol) in glacial acetic acid (125 mL) was added dropwise a solution of hydroxylamine hydrochloride (6.45 g, 0.093 mol) in water (32 mL) over 10 minutes, and the mixture was stirred at 60° C. for 25 hours. The mixture was allowed to cool and partitioned between H2O (250 mL) and chloroform (400 mL). The organic layer was washed (saturated NaCl), dried (MgSO4), and rotoevaporated. The residue was dissolved (toluene), rotoevaporated, and the solid recrystallized from toluene to give a white solid, yield 5.62 g (43%), mp 119°-122° C.
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH2:4].C([O-])([O-])=O.[K+].[K+].[OH-].[K+].[CH:23]1[CH:28]=[CH:27][C:26]([CH2:29][O:30][C:31](Cl)=[O:32])=[CH:25][CH:24]=1>O.C1COCC1>[NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][NH:4][C:31]([O:30][CH2:29][C:26]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCc1ccccc1)C(=O)O
Temperature: -5 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A stirring mixture of the N-Boc-Dap-OH 1 (10.00 g, 49.02 mmol), THF (90 mL), water (30 mL), K2CO3 (13.53 g, 98.04 mmol) and KOH (2.75 g, 49.02 mmol) was cooled to −5° C. Cbz-Cl solution (50 wt % in toluene, 25 mL, 73.53 mmol) was then added dropwise over a period of an hour. The mixture was allowed to stir for 8 h before being concentrated under reduced pressure to remove the THF. The aqueous residue was extracted with diethyl ether (50 mL), acidified to pH 4 by solid citric acid and the resulting precipitate was extracted by CH2Cl2 (2 50 mL). Combined organic layers were dried (Na2SO4) and evaporated to furnish the free acid 2 (15.57 g, 94% yield) as a gummy white solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ10.76 (1H), 7.25 (5H), 6.24, 5.67 (2H), 5.85 (1H), 5.08, 5.02 (2H), 4.36-4.23 (1H), 3.63-3.35 (2H), 1.38 (9H); 13C NMR (75 MHz, CDCl3)δ 173.5, 157.5, 156.2, 136.4, 128.6, 128.2, 80.6, 67.3, 54.4, 42.9, 28.6.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([CH2:9][OH:10])=[CH:7][N:8]=1.CCN(CC)CC.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:21][S:18]([O:10][CH2:9][C:6]1[S:5][C:4]([Br:3])=[N:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cnc(Br)s1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cnc(Br)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (2-bromo-thiazol-5-yl)-methanol (621 mg, 3.20 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.60 mL, 4.23 mmol) followed by DMAP (39 mg, 0.32 mmol) and Ms-Cl (0.33 mL, 4.15 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (2-bromothiazol-5-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (15 mL) and treated with NaN3 (223 mg, 3.40 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer washed with water (2×), dried over MgSO4, filtered and concentrated under reduced pressure to give crude 5-(azidomethyl)-2-bromothiazole as a yellow oil. To a solution of the crude azide in THF (12 mL) were added polymer-supported Ph3P (1.2 eq.) and water (4 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. 1N NaOH/aq. sat. NaHCO3 and the layers separated. The aq. layer was extracted with EA and the combined org. extracts dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 01: tR=0.16 min; [M+CH3CN+H]+=233.91.
Reaction SMILES: [C:1]1([SH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([S:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Sc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2cccc3ccccc23)ccn1
Yield: 89.2 %

Procedure:
Using the method of Example 3, Step A, naphthalen-1-thiol (909 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to afford 2-chloro-4-(naphthalen-1-ylthio)pyridine (1.53 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.22 (d, 1H), 8.03-8.05 (m, 2H), 7.89-7.96 (m, 2H), 7.54-7.59 (m, 3H), 6.82 (s, 1H), 6.72 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>CN(C=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCC1CC1)c1ccc(Cl)s1
Temperature: 70 °C

Procedure:
To a solution of 5-chlorothiophene-2-carboxylic acid (5.00 g) in DMF (50 mL) were added potassium carbonate (6.38 g) and (bromomethyl)cyclopropane (4.47 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].CO[C:26](OC)(OC)[CH2:27][C:28]([O:30]CC)=O.C1(C)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][NH2:52])=[CH:47][CH:46]=1>S(=O)(=O)(O)O.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([S:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])(=[O:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:26]1[CH2:27][C:28](=[O:30])[N:51]([C:48]2[CH:49]=[CH:50][C:45]([Cl:44])=[CH:46][CH:47]=2)[N:52]=1
Reactant: CCOC(=O)CC(OC)(OC)OC
Reactant: CCCCCCCCCCCCS(=O)(=O)c1ccc(N)c(Cl)c1
Reactant: NNc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCCCCCCCCS(=O)(=O)c1ccc(NC2=NN(c3ccc(Cl)cc3)C(=O)C2)c(Cl)c1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
A stirred mixture of 2-chloro- 4-dodecylsulfonylaniline (21.9 g, 0.061 moles), ethyl 3,3,3-trimethoxypropionate (11.7 g, 0.061 moles) and toluene (100 ml) was heated in an oil-bath at 110° C. until solution was attained. Concentrated sulfuric acid (4 drops) was added and the stirred mixture was heated for 2-25 hours allowing volatiles to distill off. The solution was cooled and the solvent was removed on the rotavapor to leave an oil. The oil was dissolved in glacial acetic acid (100 ml) and 4-chlorophenylhydrazine (8.7 g, 0.061 moles) was added. The mixture was stirred at room temperature for 22 hours. Then the resulting solid was filtered off, washed with methanol and dried. The solid was purified by trituration with ethyl acetate to give the product as a pale yellow solid weighing 20.1 g (60%).
Reaction SMILES: C1N=CN([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])C=1.[CH3:13][N:14]([CH2:16][CH2:17][OH:18])[CH3:15].Cl.NCC1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:13][N:14]([CH3:15])[CH2:16][CH2:17][O:18][C:6]([NH:8][CH2:9][C:10]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:7]
Reactant: CN(C)CCO
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CNC(=O)OCCN(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
A solution of carbonyl diimadzole (CDI) (609 mg, 3.76 mmol) in pyridine (5 mL) was treated with neat dimethylaminoethanol (400 μL, 3.98 mmol) and the mixture was stirred for 15 h at room temperature. Methyl 4-(aminomethyl)benzoate hydrochloride (217) (794 mg, 3.82 mmol) was then added and the reaction mixture was stirred for further 7 h, diluted with DCM, washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated to produce title compound 218 as a white solid (1.16 g, >100% yield, crude, used without additional purification).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:19]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: CCOC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21

Procedure:
In analogy to the procedure described in example 5 f], (6-hydroxy-indol-1-yl)-acetic acid ethyl ester was reacted with [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 5 e]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester as colorless crystals.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]1[CH:14]([CH3:17])CO.S(Cl)([Cl:20])=O.[CH:22]([Cl:25])(Cl)Cl>>[Cl:20][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]1[CH:14]([CH3:17])[CH2:22][Cl:25]
Reactant: CC(CO)N1C(=O)c2ccccc2CC1CO
Reactant: ClC(Cl)Cl
Reactant: O=S(Cl)Cl
Product: CC(CCl)N1C(=O)c2ccccc2CC1CCl
Yield: 69 %

Procedure:
3-(Hydroxymethyl)-2-(1-hydroxypropan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (from Isomer B, 0.20 g, 0.85 mmol) in chloroform (7.6 ml) was added to a stirring solution of thionyl chloride (1.8 ml) in chloroform (10 ml). After refluxing overnight the condenser was removed and the majority of the solvent allowed to evaporate over the next 4 h. The residue was purified by flash chromatography (SiO2, CH2Cl2 to 50% EtOAc in CH2Cl2) affording pure product (0.16 g, 69% yield). MS (ESI) 273/275 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C@@H:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C@H:12]([C:23]([OH:25])=[O:24])[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:22][C:17]1[CH:16]=[C:15]([C@H:13]2[C@H:12]([C:23]([O:25][CH3:26])=[O:24])[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14]2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)[C@@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a solution of (6R,7R)-4-(tert-butoxycarbonyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-7-carboxylic acid (3.11 g) in DMF (10 mL) were added potassium carbonate (1.32 g) and methyl iodide (0.748 mL). The mixture was stirred at room temperature for 2 hr under nitrogen purging, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-50%)) to give the title compound (2.86 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24].[NH2:25][C:26]1[CH:38]=[CH:37][C:29]2[N:30]([CH3:36])[CH:31]=[CH:32][S:33](=[O:35])(=[O:34])[C:28]=2[CH:27]=1.Cl>CN1C(=O)CCC1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:25][C:26]3[CH:38]=[CH:37][C:29]4[N:30]([CH3:36])[CH2:31][CH2:32][S:33](=[O:35])(=[O:34])[C:28]=4[CH:27]=3)=[N:15][CH:16]=2)[N:11]([CH3:23])[C:10]1=[O:24]
Reactant: CN1C(=O)N(c2c(F)cccc2Br)Cc2cnc(S(C)(=O)=O)nc21
Reactant: CN1C=CS(=O)(=O)c2cc(N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: CN1CCS(=O)(=O)c2cc(Nc3ncc4c(n3)N(C)C(=O)N(c3c(F)cccc3Br)C4)ccc21
Temperature: 120 °C
Yield: 31.1 %

Procedure:
83 mg 3-(2-bromo-6-fluorophenyl)-3,4-dihydro-7-methanesulphonyl-1-methyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 85 mg 7-Amino-4-methyl-4H-benzo[1,4]thiazin-1,1-dioxide (starting material n)) in 0.8 ml NMP were treated with 0.2 ml 2M HCl in ether and heated to 120° C. for 6 hrs. The mixture was purified by preparative HPLC-MS to yield 34 mg of the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(Cn2cc(I)cn2)cc1
Temperature: 60 °C
Yield: 88.2 %

Procedure:
According to Scheme 9 Step 1: A suspension of 4-iodo-1H-pyrazole (26.3 mmol, 5.11 g), 1-(chloromethyl)-4-methoxybenzene (29.0 mmol, 3.95 mL) and K2CO3 (39.5 mmol, 5.46 g) in acetonitrile (150 mL) was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel using DCM as eluent to afford 4-iodo-1-(4-methoxybenzyl)-1H-pyrazole (23.2 mmol, 7.3 g, 88%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Br:27][CH2:28][CH2:29][CH2:30][CH2:31]Br>CC(C)=O.CCOCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20][CH2:31][CH2:30][CH2:29][CH2:28][Br:27])=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(O)ccc21
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(OCCCCBr)ccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 49.4 %

Procedure:
290 mg (1 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester in 5 ml acetone were treated with 320 mg (3 mmol) K2CO3 (powdered) and 0.23 ml (2 mmol) 1,4-dibromobutane. The suspension was stirred at 50° C. for 4 h, cooled to RT, and was diluted with ether and water. The aqueous phase was extracted with ether, the organic phases were washed with water and dried over Na2SO4. Column chromatography on silica gel with hexane/EtOAc 9:1 yielded 210 mg (49%) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as colorless solid, MS: 423 (M, 1Br, 1Cl).