Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([NH2:12])=[N:10][N:11]=2)[N:8]=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>O>[N:13]1([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([C:9]([NH2:12])=[N:10][N:11]=3)[N:8]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Nc1nnc2ccc(Cl)nn12
Reactant: C1CCNCC1
Agent: Br
Solvent: O
Product: Nc1nnc2ccc(N3CCCCC3)nn12

Procedure:
6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001; 100 mg) were initially charged in water (1 ml) and admixed with piperidine (260 μl) with stirring. Thereafter, the mixture was heated to reflux for 1 h and, after cooling, freed of the solvent. Subsequently, the mixture was admixed with water and the solid formed was filtered off with suction and dried. The mother liquor was dried and admixed with a little water. The solid obtained was filtered off with suction and dried. The filtrate was then extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. The three resulting solid fractions were combined and gave rise to 56 mg of the title compound.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccn3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccn3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-pyridin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (25 mg, 0.065 mmol), β-alanine (863 mg, 9.69 mmol) and NaOMe solution (15.5 mL, 7.75 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in water and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 1 M HCl, and the resulting precipitate was isolated by filtration to give 9 mg of the title compound. MS: (+) m/z 445.33 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO[C:16](=O)[C:17]1C=C(N(CCC)CCC)C=CC=1N.S(Cl)(Cl)=O>C(O)C>[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: CCCN(CCC)c1ccc(N)c(C(=O)OC)c1
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (10.0 g) was dissolved in ethanol (100 ml). Thionyl chloride (20 ml) was added dropwise to the solution at 0° C., and the mixture was then heated under reflux with stirring for 48 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution under ice cooling. The cooled solution was subjected to separatory extraction with ethyl acetate. The organic layer was dried over sodium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-chloro-2-nitro-benzoic acid ethyl ester as a useful intermediate (11.0 g, yield 97%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[CH2:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([CH2:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cnc(CCC(F)(F)F)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1CCC(F)(F)F
Yield: 57 %

Procedure:
The title compound is prepared in 57% yield (700 mg, white solid) from 1-(5-methyl-6-(3,3,3-trifluoropropyl)pyridin-3-yl)ethanone (850 mg, 3.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (668 mg, 5.51 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:12][C@H:13]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[C:14]([CH3:17])([OH:16])[CH3:15].C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C@H:13]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[C:14]([CH3:17])([OH:16])[CH3:15])[C:5]2[S:10][CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(O)[C@H](N)c1ccc(F)cc1
Reactant: Clc1nc(Cl)c2c(n1)CCS2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(O)[C@H](Nc1nc(Cl)nc2c1SCC2)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 28.5 %

Procedure:
533 mg 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine, 850 mg (R)-1-amino-1-(4-fluoro-phenyl)-2-methyl-propan-2-ol and 1.3 ml diisopropylethylamine are suspended in 9.8 ml dioxane. The reaction mixture is stirred for 2 hours in the microwave at 80° C. and then evaporated to dryness. The residue is mixed with water. The precipitate formed is suction filtered and purified by chromatography (silica gel, petroleum ether/ethyl acetate 100/0 to 60/40). 260 mg of the product are obtained as a solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[N:24]=[C:23]([C:25](Cl)=[O:26])[CH:22]=[C:21]([Cl:28])[N:20]=1>C(Cl)Cl>[Cl:18][C:19]1[N:24]=[C:23]([C:25]([NH:2][C@@H:3]([CH3:8])[C:4]([O:6][CH3:7])=[O:5])=[O:26])[CH:22]=[C:21]([Cl:28])[N:20]=1
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)NC(=O)c1cc(Cl)nc(Cl)n1
Yield: 33.2 %

Procedure:
To a mixture of (S)-methyl 2-aminopropanoate hydrochloride (1.397 g, 10.01 mmol) in DCM (80 mL) was added iPr2NEt (4.35 mL, 24.97 mmol). The mixture was stirred for a few minutes and a solution of the 2,6-dichloropyrimidine-4-carbonyl chloride (2.107 g, 9.97 mmol) in DCM (20 mL) was added over a period of 1 minute. After stirring overnight, the reaction was concentrated in vacuo to a residue. The residue was chromatographed over silica gel using 10-40% EtOAc in hexanes. The product fractions were evaporated in vacuo to give (S)-methyl 2-(2,6-dichloropyrimidine-4-carboxamido)propanoate as a yellow oil (0.921 g, 3.31 mmol, 33% yield). LC/MS: m/z=278.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:18]=[CH:17][C:10]([O:11][CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25]O.S(=O)(=O)(O)O.O>C(Cl)(Cl)Cl>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][O:14][C:13](=[O:15])[CH:12]([O:11][C:10]1[CH:17]=[CH:18][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:20][CH:19]=2)=[CH:8][CH:9]=1)[CH3:16]
Reactant: OCCCCCl
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2)cc1)C(=O)OCCCCCl

Procedure:
24.4 g=0.08 mol of 2-[4'-(4"-chlorophenoxy)phenoxy]-propionic acid, 10.8 g=0.1 mol of 4-chlorobutanol and 2 ml concentrated sulfuric acid in 50 ml chloroform were refluxed for 6 hours with azeotropic distillation of the reaction water. After cooling, the reaction mixture was washed twice with 100 ml water, neutralized with bicarbonate solution and washed with water until it was free from salt. After drying over calcium chloride and distillation of the solvent, 27.0 g=88% of the theory of 2-[4'-(4"-chlorophenoxy)phenoxy]-propionic acid 4-chlorobut-1-yl ester were obtained having a refractive index nD24 of 1.5517. ##STR16##
Reaction SMILES: [OH:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:25])=[O:24]
Reactant: CCOC(=O)C(O)c1cccs1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(OS(C)(=O)=O)c1cccs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 2-hydroxy-2-(thiophen-2-yl)acetate (I26) (4.58 g, 24.6 mmol) was dissolved in dry DCM (125 ml) and cooled at 0° C. DIPEA (5.15 ml, 29.5 mmol) and methanesulphonyl chloride (2.11 ml, 27.1 mmol) were added, and the resulting solution was stirred at room temperature for 1 hour. DIPEA (0.86 ml, 4.92 mmol) and methanesulphonyl chloride (0.19 ml, 2.46 mmol) were added again. After 1 additional hour, a third portion of DIPEA (0.43 ml, 2.46 mmol) and methanesulphonyl chloride (77 ul, 0.98 mmol) was added. After 1 hour, the reaction was completed. The mixture was diluted with DCM, washed with sat. NaHCO3, water and brine, dried (Na2SO4), filtered, and evaporated. The resulting oil was used for the next step without any further purification.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:7]=[CH:8][C:9](Cl)=[N:10][CH:11]=1)=[O:5].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[N:10][CH:11]=1)=[O:5]
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CON(C)C(=O)c1ccc(-n2ccnc2)nc1
Temperature: 140 °C
Reaction time: 24 h
Yield: 70.6 %

Procedure:
A suspension of O,N-dimethyl-2-chloropyridine-5-hydroxamic acid (10.0 g, 50 mmol-see Preparation 22(i)), imidazole (4.1 g, 60 mmol) and potassium carbonate (6.9 g, 50 mmol) in N,N-dimethylacetamide (200 ml) was stirred at 140° C. for 24 hours. The mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was washed with water (100 ml) and brine (50 ml) then dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica using gradient elution with ethyl acetate/hexane (1:1,1:0). Fractions containing the desired product were combined and evaporated under reduced pressure to give the title compound (8.2 g, 71%) as an orange oil. A sample was triturated with ether to afford a colourless solid, m.p. 69-70° C.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:27])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]1[CH2:15][CH2:16][C:17]1[N:26]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[N:19]2[N:18]=1.[CH3:28][NH:29][CH3:30].CO>CS(C)=O>[CH3:28][N:29]([CH3:30])[CH2:2][C@H:3]([OH:27])[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[N:7]=[C:6]1[CH2:15][CH2:16][C:17]1[N:26]=[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([CH3:25])[N:19]2[N:18]=1
Reactant: CNC
Reactant: Cc1cccc2nc(CCc3nc(-c4cccs4)cn3C[C@@H](O)CCl)nn12
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cccc2nc(CCc3nc(-c4cccs4)cn3C[C@@H](O)CN(C)C)nn12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (R)-1-Chloro-3-{2-[2-(5-methyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-ethyl]-4-thiophen-2-yl-imidazol-1-yl}-propan-2-ol (2 mg, 0.005 mmol) in DMSO (0.5 mL) was added a 2M solution of dimethylamine in methanol (100 μL, 0.2 mmol), the reaction vessel was capped and stirred at 100° C. for 30 minutes. The volatiles were removed in vacuo and the residue purified by preparative LC-MS to yield the title compound. 100% yield, LC-MS: m/z=411.4 (MH+), tR=0.33 minutes, method B.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14].[C-:17]#[N:18].[Na+]>CN(C=O)C>[C:17]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:15][CH3:16])=[O:14])#[N:18]
Reactant: CNC(=O)c1cnn(-c2ccccc2)c1Br
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccc2)c1C#N
Temperature: 100 °C
Yield: 39.8 %

Procedure:
A solution of 5.6 g of 5-bromo-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide and 2 g of sodium cyanide in 30 ml of DMF was heated at approximately 100° C. for 24 hours. An additional 2 g of sodium cyanide was next added to the reaction mixture which was then heated for an additional 24 hours at 100° C. The solution was poured into ice water and the precipitated solid was collected by filtration. The product thus isolated was recrystallized from 3A ethanol to provide 1.8 g of 5-cyano-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. MP=203°-204° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[F:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Reactant: OB(O)c1cccc(-c2ccccn2)c1F
Product: Fc1c(-c2ccccn2)cccc1-c1cnc2nc(C(F)(F)F)ccn12

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2-fluoro-3-(pyridin-2-yl)benzeneboronic acid as described in Example 1 to give 3-[2-fluoro-3-(pyridin-2-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as a white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (360 MHz, DMSO) 7.61-7.71 (3H, m), 7.87-7.91 (1H, m), 8.07-8.11 (2H, m), 8.20-8.24 (1H, m), 8.42 (1H, s), 8.87 (1H, dd, J 5 and 1), 9.42 (1H, dd, J 7 and 3); m/z (ES+) 359 (M++H).
Reaction SMILES: O[CH:2]([C:6]1[CH:21]=[CH:20][C:9]([O:10][CH2:11][C:12]2[CH:16]=[CH:15][S:14][C:13]=2[C:17]([OH:19])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].[F:22][C:23]([F:34])([F:33])[C:24]([O:26]C(=O)C(F)(F)F)=[O:25].[K+].[Br-]>ClCCl.C(OCC)(=O)C>[F:22][C:23]([F:34])([F:33])[C:24]([O:26][CH2:5][CH2:4][CH2:3][CH2:2][C:6]1[CH:7]=[CH:8][C:9]2[O:10][CH2:11][C:12]3[CH:16]=[CH:15][S:14][C:13]=3[C:17](=[O:19])[C:20]=2[CH:21]=1)=[O:25]
Reactant: CCCC(O)c1ccc(OCc2ccsc2C(=O)O)cc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1c2cc(CCCCOC(=O)C(F)(F)F)ccc2OCc2ccsc21
Reaction time: 48 h

Procedure:
A stirred suspension of 14.33 g (0.468 mol) of 3-[4-(1-hydroxybutyl)phenoxy]methyl-2-thiophenecarboxylic acid and 150 ml of anhydrous CH2Cl2 was treated with one portion of trifluoroacetic anhydride (22.60 g, 0.107 mol). The suspended material rapidly dissolved and the stirred solution was heated under reflux for four hours. After standing two days at ambient temperature, the reaction was quenched with water (70 ml) and washed with 50 ml of 5% NaHCO3 solution. The dried (Na2SO4) organic phase was concentrated to an oil, which was further dried by azeotropic distillation of toluene. The oil was dissolved in approximately 15 ml of isopropanol, seeded with product previously prepared on a smaller scale, and stirred until a thick crystalline mass formed. The mass was triturated with isopropanol, followed by vacuum filtration. The filter cake was dried in vacuo at 40° C. to afford 15.08 g (83.8%) of almost colorless crystals, m.p. 65.5°-67° C. The material appeared pure by TLC (siica gel, ethyl acetate, Rf =0.70; dichloromethane, Rf =0.51) and the IR (KBr), 1H-NMR (CDCl3) and MS (M+, 384) were consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([CH3:9])[CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH:10](=[N:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(O)c(N)c1
Solvent: CO
Product: Cc1ccc(O)c(N=Cc2ccccc2)c1
Yield: 63.9 %

Procedure:
A solution of 2-amino-p-cresol (1.23 g, 10 mmol) and benzaldehyde (1.06 g, 10 mmol) in methanol (10 ml) was heated at reflux for 2 hrs then cooled in an ice bath. The product was filtered off, washed with a little cold methanol and dried to yield 1.35 g of 2-benzylideneamino-4-methylphenol 54.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([OH:20])=O)=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.Cl.[CH3:23][NH2:24]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:24][CH3:23])=[O:20])=[C:13]([C:15]([NH2:16])=[O:17])[N:14]=[C:7]3[C:6]=2[CH:21]=1
Reactant: NC(=O)c1nc2n(c1C(=O)O)CCOc1ccc(Br)cc1-2
Reactant: CN
Agent: Cl
Solvent: O
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2

Procedure:
10-Bromo-3-iodo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (5 g) was subjected similar to as described in Example 6 to yield 4.2 g of methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate. Methyl 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylate (0.52 g) was subjected to lithium hydroxide water/THF to give 0.44 g of 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid. 10-bromo-2-carbamoyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.44 g) was reacted with Methylamine hydrochloride similar to as described in Example 2 to afford 314 mg 10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following triteration from water. 10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide (0.1 g) was then reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol similar to as described in Procedure G to afford 43.9 mg of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 436 (M)+. 1H NMR (400 MHz, DMSO) δ 11.06 (q, J=4.3 Hz, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.40 (dd, J=8.5, 2.0 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 6.36 (s, 1H), 5.04-4.91 (m, 2H), 4.57-4.44 (m, 2H), 2.81 (d, J=4.5 Hz, 3H), 2.41 (s, 3H), 1.81 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][CH2:7][CH2:8]OS(C)(=O)=O)=[O:4].Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=2)=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][N:27]([CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCCNC(=O)C(F)(F)F
Reactant: Clc1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCCCN1CC=C(c2ccc(Cl)cc2)CC1)C(F)(F)F
Yield: 44.9 %

Procedure:
Methanesulfonic acid 3-(2,2,2-trifluoroacetylamino)-propyl ester (4.51 g, 18.10 mmol), 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (4.20 g, 18.25 mmol) and triethylamine (5.6 mL, 40.2 mmol) in ethanol (100 mL) were refluxed for 18 hours. The mixture was concentrated, redissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated on to silica gel. Flash chromatography using first an ethyl acetate/hexanes gradient followed by 3% methanol/ethyl acetate gave N-{3-[4-(4-chloro-phenyl)-3,6-dihydro-2H-pyridin-1-yl]-propyl}-2,2,2-trifluoro-acetamide (2.82 g, 45%) as a white solid. Mp. 105-107° C.; NMR CDCl3 δ 9.58 (br s, 1H), 7.27-7.24 (m, 4H), 6.01-5.98 (m, 1H), 3.49 (g, J=5.3 Hz, 2H), 3.20-3.17 (m, 2H), 2.77 (t, J=5.7 Hz, 2H), 2.73-2.69 (m, 2H), 2.55-2.51 (m, 2H), 1.80 (p, J=3.6 Hz, 2H); 13C NMR CDCl3 δ 138.80, 134.41, 133.15, 128.52, 126.22, 120.99, 57.72, 52.80, 50.15, 40.96, 27.61, 23.23; IR (KBr) 3300, 3099, 2981, 2953, 2925, 2907, 2810, 2758, 2734, 1695, 1558, 1494, 1469, 1444, 1352, 1184, 1137, 1118, 1097,801,722,692.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:17][CH2:18][O:19][C:20](=[O:33])[CH:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([O:12][CH2:17][CH2:18][O:19][C:20](=[O:33])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH3:22])=[O:11])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(4-nitrophenoxy)-propionic acid 29 (25 g, 118.5 mmol) and 2-(4-nitrophenoxy)propionic acid 2-hydroxyethyl ester 30 (25 g, 108 mmol) in anhydrous dichloromethane (625 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (40 g, 194 mmol) in anhydrous dichloromethane (250 ml). The reaction mixture was stirred at room temperature for 8 hours. The solids were filtered off and dichloromethane distilled off to get crude 31. The crude 31 was purified by column chromatography on silica gel using hexane as eluant to get pure 31 (17 g, 35.1%) as a white powder with an m.p. between 117.5-120.5° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[C:11]=2[CH:10]=[C:9]1[CH3:21])=O)(C)(C)C.O.[OH-].[Na+]>CO>[CH3:21][C:9]1[NH:8][C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:18]([OH:20])=[O:19])[C:11]=2[CH:10]=1
Reactant: Cc1cc2c(CC(=O)O)cccc2n1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(CC(=O)O)cccc2[nH]1
Temperature: 50 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a mixture of 1-t-butoxycarbonyl-2-methylindole-4-acetic acid (96.3 g) in methanol (200 ml)—water (100 ml) was added dropwise 5N aqueous solution of sodium hydroxide (200 ml) at room temperature, and the mixture was stirred at 50° C. for 3 hours and then stirred at room temperature for 12 hours. The reaction mixture was extracted with hexane—ether. The aqueous layer was adjusted to acidic condition with hydrochloric acid and then extracted with ethyl acetate. The extraction was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure to give the title compound (53.9 g; crude).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2nc3ccc(Br)cc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc2nc(OC3CCNCC3)sc2c1
Reaction time: 2 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 4-(6-bromobenzo[d]thiazol-2-yloxy)piperidine-1-carboxylate (257 mg, 0.622 mmol) in CH2Cl2 (5 mL) was added TFA (0.719 mL, 9.33 mmol). After 2 h, the reaction mixture was diluted with DCM and washed with 1N NaOH and then brine, dried over Na2SO4, filtered and then concentrated under reduced pressure to obtain Compound 1B as a light yellow solid (190 mg, 0.607 mmol, 98% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 7.75 (1H, d, J=1.9 Hz), 7.48-7.52 (1H, m), 7.43-7.47 (1H, m), 5.21-5.29 (1H, m), 3.15 (2H, dt, J=12.9, 4.7 Hz), 2.80 (2H, ddd, J=12.7, 9.5, 3.2 Hz), 2.10-2.22 (2H, m), 1.71-1.84 (2H, m), 1.47 (1H, br. s.).