Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([F:27])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:28][C:29]([OH:34])([C:32]#[CH:33])[CH2:30][OH:31].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[C:3]([F:27])[C:2]([C:33]#[C:32][C:29]([OH:34])([CH3:28])[CH2:30][OH:31])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1cc(F)c(Br)cc1-2
Reactant: C#CC(C)(O)CO
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1-c1nc(C2CC2)n[nH]1)CO
Yield: 47.1 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-(3,4-dihydroxy-3-methyl-but-1-ynyl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-9-fluoro-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 2-methylbut-3-yne-1,2-diol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 30 mg of the titled compound (47.1% yield). M+1=453.0.
Reaction SMILES: C([N:5]1[C:9]([N:10]([NH:19][C:20](=[O:30])[CH2:21][C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=2)[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][C:7]([C:31]([CH3:34])([CH3:33])[CH3:32])=[N:6]1)(C)(C)C>C(O)=O.O>[C:31]([C:7]1[CH:8]=[C:9]([N:10]([NH:19][C:20](=[O:30])[CH2:21][C:22]2[CH:23]=[C:24]([F:29])[CH:25]=[C:26]([F:28])[CH:27]=2)[C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:5][N:6]=1)([CH3:32])([CH3:33])[CH3:34]
Reactant: CCOC(=O)CC(=O)N(NC(=O)Cc1cc(F)cc(F)c1)c1cc(C(C)(C)C)nn1C(C)(C)C
Solvent: O
Solvent: O=CO
Product: CCOC(=O)CC(=O)N(NC(=O)Cc1cc(F)cc(F)c1)c1cc(C(C)(C)C)n[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of compound 23 (Example 119) was refluxed in 3 mL of formic acid for 20 min. The mixture was cooled to 25° C. and diluted with 12 mL of distilled water. The resulting precipitate was collected by filtration and dried in a stream of air. It was suspended in 5 mL of chloroform and filtered. The solvent was evaporated from the filtrate at reduced pressure. The residue was stirred with 5 mL of tert-butyl methyl ether for one hour, and then recovered by filtration. The product was obtained as a white powder. Analysis gave 56.84% C, 5.87% H, 13.28% N.
Reaction SMILES: C([N:8]1[CH2:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][C@@H:9]1[CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1>[Pd].CC(O)=O.[H][H]>[CH2:27]([O:26][CH2:25][C@H:9]1[CH2:10][N:11]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:13][NH:8]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: [H][H]
Reactant: CC(C)C[C@@H]1CN(Cc2ccccc2)[C@@H](COCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@@H]1CN[C@@H](COCc2ccccc2)CN1C(=O)OC(C)(C)C
Yield: 89.4 %

Procedure:
10% Palladium on carbon (0.8 g) was added to a solution of (2R,5R)-1-benzyl-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-5-(2-methylpropyl)piperazine (8.1 g) in AcOH (80 ml), and the mixture was hydrogenated in hydrogen at 3 atm for 4 hours at ambient temperature. The catalyst was removed by filtration through a celite pad and the filtrate was washed with AcOH. The filtrate and combined washings were concentrated in vacuo, and the residue was partitioned by dissolving same in saturated aqueous NaHCO3 solution and AcOEt. The organic layer was washed with NaCl solution, dried over MgSO4, and concentrated in vacuo to give 5.8 g of (2R,5R)-2-benzyloxymethyl-4-(tert-butoxycarbonyl)-5-(2-methylpropyl)piperazine as an oil.
Reaction SMILES: [B-](F)(F)(F)F.N#[O+].[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18](N)=[CH:17][CH:16]=2)[N:12]=[C:11]([C:22]([O:24][CH3:25])=[O:23])[C:10]=1[CH:26]=[CH2:27].[I-:28].[Na+].[O-]S([O-])=O.[Na+].[Na+]>ClCCl.O1CCOCC1.O>[NH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([I:28])=[CH:17][CH:16]=2)[N:12]=[C:11]([C:22]([O:24][CH3:25])=[O:23])[C:10]=1[CH:26]=[CH2:27]
Reactant: [I-]
Reactant: C=Cc1c(N)nc(-c2ccc(N)cc2)nc1C(=O)OC
Agent: F[B-](F)(F)F
Agent: N#[O+]
Agent: O=S([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: C=Cc1c(N)nc(-c2ccc(I)cc2)nc1C(=O)OC
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a 50-mL round bottom flask, equipped with a stir bar, was added nitrosyl tetrafluoroborate (78 mg, 0.67 mmol) and dichloromethane (2.0 mL). The flask was cooled in a ice water bath and placed under N2 atmosphere. Then methyl 6-amino-2-(4-aminophenyl)-5-vinylpyrimidine-4-carboxylate (180 mg, 0.666 mmol) in dichloromethane (2.5 mL) was added dropwise. The reaction was allowed to stir for 60 min. Then sodium iodide (499 mg, 3.33 mmol) in a minimal amount of H2O was added, followed by dioxane (1.0 mL). The reaction was allowed to stir for 18 hrs at room temperature. The reaction mixture was poured into saturated Na2SO3 solution and extracted with ethyl acetate (3×50 L). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (Silica gel, 0-30% EtOAc in Hexanes), and reverse phase chromatography to afford the title compound as a light yellow solid (0.068 g, 27%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:17][C:18]([OH:20])=O)[C:7]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]2[S:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:18](=[O:20])[CH2:17][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2Sc2ccccc21

Procedure:
78.4 g of 3-nitro-6-(phenylthio)-phenylacetic acid and 400 g of polyphosphoric acid are held at 105°-110° C for 90 minutes with stirring. The mixture is subsequently diluted with ice and water and extracted with benzene. The organic phase is washed successively with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. There is obtained 10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-one of melting point 171°-172° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[Cl-].[Cl:14]CC(O)[CH2:17][N+:18](C)([CH3:20])[CH3:19].[OH-].[Na+]>>[Cl-:14].[OH:1][CH2:2][CH2:3][CH2:5][N+:18]([CH3:20])([CH3:19])[CH3:17].[OH:12][CH2:11][C@@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: C[N+](C)(C)CC(O)CCl
Agent: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Cl-]
Agent: [Na+]
Product: C[N+](C)(C)CCCO

Procedure:
Herein is provided a synthesis procedure for the chloride salt of hydroxypropyltrimonium sorbitol (also referred to as ‘Sorbitol Monoquat’). A round bottom 250 ml flask was fitted with a mechanical stirrer. Into the flask was charged a mixture of sorbitol (10 g, 55.0 mmol) and 3-chloro-2-hydroxypropyl trimethylammonium chloride (Quat 188®) (15 ml, 55.0 mmol). One molar sodium hydroxide (55.0 ml, 55.0 mmol) was then added to the charged mixture. The resultant solution was stirred at room temperature for 18 hours. Water was then removed under reduced pressure at 50° C. yielding a heterogeneous colorless syrup. Filtration through glass wool afforded sorbitol hydroxypropyltrimethylammonium chloride as a homogeneous clear syrup: m/z (ESI; M+-Cl−) 298.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[OH:32])=[CH:21][C:20]=3[OH:33])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:34](Cl)(=[O:36])[CH3:35].N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]1([C:11]2[N:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]4[O:32][C:34](=[O:36])[CH3:35])=[CH:21][C:20]=3[OH:33])[N:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cc(OC2CCCCC2O)ccc1-c1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)OC1CCCCC1Oc1ccc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c(O)c1
Reaction time: 6 h

Procedure:
A mixture of 13.0 g (29.6 mmol) of 2,4-diphenyl-6-(2'-hydroxy4'-(2"-hydroxycyclohexyloxy)phenyl)-1,3,5-triazine, 7.0 g (89.2 mmol) of acetyl chloride (Fluka, 99%) and 0.6 g (7.6 mmol) of pyridine in 140 ml of toluene (Merck, 99.5%) is stirred under nitrogen and held at 50° C. for 6 h.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].[C:5]([N:9]=[N:10][C:11]1([N:17]=[C:18]=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([N:9]=[N:10][C:11]1([NH:17][C:18]([O:2][CH3:1])=[S:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=S)NC1(N=NC(C)(C)C)CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 50 ml of methanol in a 125 ml erlenmeyer flask stirred with a magnetic stirrer, was slowly added 2.1 grams (0.05 moles) of 57% sodium hydride. The reaction mixture was cooled back to 25° C. and 11.2 grams (0.05 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane was added dropwise over 5 minutes. The reaction mixture was stirred 24 hours at room temperature, poured into 300 ml water and the product extracted with 100 ml pentane. The pentane extract was washed with water, 10% NaHCO3 solution, dried over anhydrous Na2SO4, filtered, and the pentane evaporated under reduced pressure to leave 9.2 grams of a mushy semi-solid. The semi-solid was slurried in cold pentane and filtered. The solids were dried and weighed 5.6 grams (43.5% crude yield) and melted at 79°-82° C. The infrared spectrum of the product had a strong broad band at 1530 cm-1 and a sharp NH band at 3250 cm-1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.F[C:20]1[CH:21]=[C:22]([CH:32]=[CH:33][C:34]=1[N+:35]([O-:37])=[O:36])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>C(#N)C>[CH3:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][O:23][C:22]2[CH:21]=[CH:20][C:34]([N+:35]([O-:37])=[O:36])=[C:33]([CH:32]=2)[NH:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:18])[F:1])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[N:26][CH:27]=1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(-c4ccc(C(F)(F)F)cc4)cc3)c2)nc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 73.6 %

Procedure:
To a flask containing (4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methanamine (107 g, 406 mmol) and 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (114 g, 406 mmol) in acetonitrile (900 mL) was added DIPEA (106 mL, 610 mmol). The stirred mixture was then warmed to 80° Celsius and held for 7 h. After cooling to RT, the resulting slurry was diluted with acetonitrile (300 mL), filtered and the resulting solids were washed with acetonitrile (200 mL). The solids were dried in a vacuum oven at 75° Celsius for 3 h to give the title compound (147.5 g, 73%). MS (ESI): mass calcd. for C27H22F3N3O3, 493.2; m/z found, 494.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.71 (bs, 1H), 8.38 (s, 1H), 8.17 (d, J=9.5, 1H), 7.69 (s, 4H), 7.58 (d, J=7.8, 2H), 7.49 (d, J=7.8, 1H), 7.43 (d, J=7.8, 2H), 7.29 (d, J=8.0, 1H), 6.35 (d, J=9.6, 1H), 6.29 (s, 1H), 5.13 (s, 2H), 4.54 (d, J=5.7, 2H), 2.30 (s, 3H).
Reaction SMILES: [Si]([N:5]=[N+:6]=[N-:7])(C)(C)C.[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19](N)=[CH:18][C:17]=1[CH:31]([CH3:33])[CH3:32])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC#N>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:19]([N:5]=[N+:6]=[N-:7])=[CH:18][C:17]=1[CH:31]([CH3:33])[CH3:32])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)c1cc(N)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: CC#N
Product: CC(C)c1cc(N=[N+]=[N-])c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 75 %

Procedure:
tBuONO (2.25 ml, 19 mmol) and TMSN3 (2 ml, 15.2 mmol) were added to a solution of 1,5-bis-benzyloxy-2-isopropyl-4-amino-benzene (1.10 g, 3.18 mmol) in CH3CN (40 ml). The reaction mixture was stirred for 1 hour at 0° C. and for 12 hours at RT. The solvent was evaporated under reduced pressure and the crude reaction mixture was purified by flash chromatography (PE/AcOEt:95/5 to 90/10). The title compound was obtained as a brown solid (890 mg, 75%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]C(C)C)=[O:10])=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>>[CH:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)nc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1ccc(C(=O)O)cn1
Yield: 100.5 %

Procedure:
In a similar manner to that described in Example 2, a reaction was carried out using isopropyl 6-isopropoxynicotinate (130 mg), which is the product of Reference example 18(a) and aqueous sodium hydroxide solution (1N, 0.87 ml) and the reaction mixture was treated to afford the title compound (106 mg) as crystals.
Reaction SMILES: [NH2:1][C@H:2]1[C:5](=[O:6])[NH:4][C@H:3]1[CH2:7][O:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].N([C@H]1C(=O)N(CC2C=CC(OC)=CC=2OC)[C@H]1C(OC)=O)=[N+]=[N-].O(CC(Cl)=O)C1C=CC=CC=1>>[CH2:23]([O:22][C:20]([NH:1][C@H:2]1[C:5](=[O:6])[NH:4][C@H:3]1[CH2:7][O:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: COC(=O)[C@H]1[C@@H](N=[N+]=[N-])C(=O)N1Cc1ccc(OC)cc1OC
Agent: O=C(Cl)COc1ccccc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)OCc2ccccc2)cc1

Procedure:
Reaction of cis-3-amino-4-oxo-2-p-toluenesulfonyloxymethylazetidine with benzyl chloroformate according to the procedure described in Preparation 2 for reaction of methyl cis-3-azido-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate and phenoxyacetyl chloride gives cis-3-benzyloxycarbonylamino-4-oxo-2-p-toluenesulfonyloxymethylazetidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[CH:20][CH:21]=1)[C:18]#[N:19])#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[CH:20][CH:21]=3)[C:18]#[N:19])[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1ccc(C#N)c(C#N)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncc(F)c3)no2)cc1C#N

Procedure:
The titled compound was prepared according to Method CB using the product of product of Example 28B (88 mg, 0.5 mmol) and product of Example 60A (76 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) 87.71 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.19 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.37 (dd, J=8.2, 2.7 Hz, 1H), 8.55 (d, J=1.4 Hz, 1H), 8.63 (d, J=2.7 Hz, 1H), 8.98 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1.[I-:32].[Cs+].II.N(OCCC(C)C)=O>CO.[Cu]I.COCCOC>[I:32][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[CH:16][N:15]=[C:14]([O:18][C:19]2[C:24]3[N:25]=[C:26]([NH:28][C:29](=[O:31])[CH3:30])[S:27][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH:13]=1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4N)ncn3)cccc2s1
Reactant: [I-]
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: CO
Solvent: COCCOC
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4I)ncn3)cccc2s1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To N-{4-[6-(2-amino-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 151), (0.25 g, 0.56 mmol) was added CsI (0.15 g, 0.56 mmol, Aldrich), I2 (0.071 g, 0.28 mmol, Aldrich), CuI (0.032 g, 0.17 mmol, Aldrich) and ethylene glycol dimethyl ether (6 mL). To the mixture was added isoamyl nitrite (0.45 mL, 3.4 mmol, Aldrich) and the reaction was stirred for 1 h at room temperature, at 65° C. for 3 h, and then at room temperature for 18 h. The reaction mixture was diluted with MeOH (2 M in NH3) and concentrated. The residue was taken up in MeOH and concentrated onto silica gel. Purification by silica gel chromatography (gradient, 0.4 to 1.3% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a white solid. Mp: 242–243° C. MS (ESI, pos. ion) m/z: 557.0 (M+1).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[H-].[Na+].[Cl:16][CH2:17][C:18]([CH2:20]Cl)=[CH2:19]>C1COCC1>[Cl:16][CH2:17][C:18](=[CH2:19])[CH2:20][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(CCl)CCl
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(CCl)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.9 %

Procedure:
Benzyl alcohol (3.5 mL, 33.6 mmol) and DMF (8 mL) were added to a suspension of NaH (60% suspension in mineral oil, 1.8 g, 43.7 mmol, washed with hexane before use) in THF (35 mL). The resulting mixture was stirred for 30 minutes at room temperature and then 1 h at reflux. The mixture was cooled to room temperature and slowly added over 1 h to a solution of 3-chloro-2-chloromethyl-propene (4.2 g, 33.6 mmol) in THF (40 mL). The reaction was stirred at room temperature for 18 h, quenched with brine/water (1:1) and extracted with Et2O. The organic phase was dried (MgSO4), filtered and concentrated. Chromatography (SiO2, EtOAc:Petrol 1:9) to give the title compound (3.1 g) as a colourless oil. 1H NMR (CDCl3): 7.46-7.29 (5H, m), 5.35 (1H, s), 5.30 (1H, d), 4.56 (2H, s), 4.24-4.06 (4H, m).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[S:49]1[CH:53]=[CH:52][N:51]=[C:50]1[NH2:54]>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH3:19])[CH:13]=[N:12]2)[C:8]([NH:54][C:50]2[S:49][CH:53]=[CH:52][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: COc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cnn(C(CC2CCCC2)C(=O)Nc2nccs2)c(=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (100 mg, 0.37 mmol) in methylene chloride (2.08 mL, 0.18M) at 25° C. was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (135.6 mg, 0.45 mmol) and N,N-diisopropylethylamine (0.196 mL, 1.12 mmol). The resulting solution was stirred at 25° C. for 2 h. After this time, the reaction was treated with thiazol-2-ylamine (49 mg, 0.48 mmol). The resulting solution was stirred at 25° C. for 1 d. After this time, the reaction was partitioned between water (75 mL) and methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 40 g, 1% methanol/methylene chloride) afforded 3-cyclopentyl-2-(4-methoxy-6-oxo-6H-pyridazin-1-yl)-N-thiazol-2-yl-propionamide as a white solid (41.4 mg, 32%); ES+-HRMS m/e calcd for C16H20N4O3S [M+H+] 349.1329, found 349.1328. 1H-NMR (300 MHz, DMSO-d6) δ ppm 0.98-7.78 (m, 9H), 1.95 (m, 1H), 2.27 (m, 1H), 3.82 (s, 3H), 5.54 (dd, J=4.5, J=10.6 Hz, 1H), 6.32 (d, Jm=2.7 Hz, 1H), 7.23 (d, J=3.6 Hz, 1H), 7.48 (d, J=3.6 Hz, 1H), 7.88 (d, Jm=2.7 Hz, 1H), 12.53 (s, 1H).
Reaction SMILES: CN(C)[C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[NH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.[C:23](O)(=[O:26])CC>>[CH:23]([C:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[NH:5][CH:4]=1)=[O:26]
Reactant: CN(C)c1c[nH]c2cccnc12
Reactant: CCC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Product: O=Cc1c[nH]c2cccnc12
Reaction time: 1 h
Yield: 32.4 %

Procedure:
A solution of 3-dimethylamino-1H-pyrrolo[3,2-b]pyridine (1.53 g) and hexamethylenetetramine (1.22 g) in 6.68 g of 66% propionic acid was added dropwise to a refluxing solution of 2.44 g of hexamethylenetetramine in 8.92 g of the same solvent. The addition was carried out over a period of one hour and the solution was refluxed 3.5 hours more. The solution was concentrated in vacuo and thereto water (30 ml), ethyl acetate (25 ml), and tetrahydrofuran (20 ml) were added. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (12 g) using a mixed solvent of dichloromethane and methanol (0.15:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a powder of 3-formyl-1H-pyrrolo[3,2-b]pyridine (0.45 g).
Reaction SMILES: [C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])([O:3]C)=O.[NH3:30]>O1CCCC1.CO>[NH2:30][C:1]([CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@@H:9]([NH:17][C:18]([C:20]2[NH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([Cl:29])=[CH:24][CH:23]=3)=[O:19])[C:7]1=[O:8])=[O:3]
Reactant: N
Reactant: COC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Solvent: CO
Solvent: C1CCOC1
Product: NC(=O)CN1C(=O)[C@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril (Example 7) (5.6 mg) was dissolved in a mixture of tetrahydrofuran (2 mL) and 2 M ammonia in methanol solution (2 mL). After stirring for 16 h at room temperature, the solvent was evaporated under vacuum and the residue was coevaporated with toluene (5 mL twice) under vacuum. Purification by reverse phase preparative HPLC provided the title compound (3.4 mg). HPLC/MS [M+H]+, 397; HPLC/MS [M+H-NH3]+, 380.