Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:6]=1[CH:7]=[CH:8][C:9]([O:11]C)=[O:10])(=[O:3])[CH3:2].[H-].[Na+].[CH3:20]OS(OC)(=O)=O.[OH-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:5]([N:4]([CH3:20])[C:1](=[O:3])[CH3:2])=[C:6]([CH:13]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)C=Cc1cc(Cl)ccc1NC(C)=O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(Cl)cc1C=CC(=O)O
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
12.8 g of methyl 2-acetamido-5-chlorocinnamate are dissolved in 200 ml of dimethylformamide/toluene (1:1), and 1.6 g sodium hydride (80% in paraffin oil) are added. Stirring is effected for 30 minutes, and at 0° 7 g of dimethylsulphate are added drop by drop. After 2 hours additional stirring at room temperature, 500 ml of water and 50 ml of 2 N sodium hydroxide solution are added followed by washing with toluene. After acidification, extraction with methylene chloride, removing of the solvent and chromatografic purification one obtains 7.6 g of 5-chloro-2-(N-methyl-acetamido)-cinnamic acid as oil. This oil is stirred for 24 hours at 100° with 100 ml of 5 N hydrochloric acid; after cooling the pH is adjusted to 8.5 with dilute sodium hydroxide solution, and 10 g of sodium bicarbonate are added. 7.5 g of 3,4-dichlorobenzoyl chloride in 50 ml of toluene are added dropwise. Working up as in Example 1(a) yields 10.8 g of 5-chloro-2-(N-methyl-3,4-dichlorobenzamido)cinnamic acid, which are reacted without further purification for 2 days at room temperature with 200 ml of methanol under addition of 4 ml of concentrated sulphuric acid. Extraction with methylene chloride and working up yield 8.3 g of the corresponding methyl ester, which is reacted analogously to (a).
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+].[OH-]>CO.O>[O:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:31])=[O:2])=[O:14])=[CH:18][CH:19]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc(COc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccc(COc2ccccc2)cc1
Reaction time: 8 h
Yield: 77.3 %

Procedure:
(R)-2-(4-Phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid methyl ester 6 (1.605 g, 3.83 mmol) was dissolved in methanol (40 ml) at room temperature. A solution of LiOH (177 mgs, 4.21 mmol) in 15 ml of H2O was then added and the mixture was stirred overnight. The mixture was diluted with H2O (50 ml). The methanol was then removed in vacuo. The aqueous residue was acidified with 4.5N HCl forming a precipitate that was filtered and dried. Recrystallization gave about 1.2 g of (R)-2-(4-phenoxymethyl-benzyloxycarbonylamino)-3-phenyl-propionic acid 7, mp. 115.9-116.7° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C@H:6]([C:18]([OH:20])=[O:19])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1)=[O:4].[N:23]([O-:25])=[O:24].[Na+].[N+]([O-])(O)=O.C(OCC)(=O)C>C(O)(=O)C.C(OC(=O)C)(=O)C>[F:1][C:2]([F:21])([F:22])[C:3]([NH:5][C@H:6]([C:18]([OH:20])=[O:19])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:17])[CH3:16])=[C:12]([N+:23]([O-:25])=[O:24])[CH:13]=1)=[O:4]
Reactant: O=N[O-]
Reactant: CC(=O)Nc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(C[C@H](NC(=O)C(F)(F)F)C(=O)O)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
63.2 g (0.2 Mol) of N-trifluoroacetyl-4-acetylaminophenylalanine are suspended in 300 ml of glacial acetic acid and 100 ml of acetic anhydride. After the solution has been cooled to 10° C., 1.5 g (0.022 Mol) of sodium nitrite are added and then 33.14 ml (0.8 Mol) of fuming nitric acid are slowly added dropwise, during which time a solution is formed. After stirring for 2 hours at 0° C. the mixture is poured onto 1 kg of ice and extracted 3 times with 250 ml of ethyl acetate. After the organic phase has been dried the mixture is concentrated by evaporation, the resulting residue is mixed twice with a mixture of 150 ml of ethyl acetate and 150 ml of toluene and evaporated down again. The residue obtained this time is combined with 100 ml of ethyl acetate cooled to -10° C., suction filtered and washed again with ethyl acetate cooled to -10° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13](Cl)=[O:14])=[CH:8][C:7]=2[CH:16]=1.[CH3:19][O:20][CH2:21][CH:22]1[NH:27][CH2:26][CH2:25][N:24]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[CH2:23]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:27]3[CH2:26][CH2:25][N:24]([CH2:28][C:29]4[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=4)[CH2:23][CH:22]3[CH2:21][O:20][CH3:19])=[O:14])=[CH:8][C:7]=2[CH:16]=1
Reactant: COCC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)Cl)=C2
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1CN(Cc2cc(OC)c(OC)c(OC)c2)CCN1C(=O)C1=Cc2cc(OC)c(OC)cc2CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 2,3-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carbonyl chloride (0.36 g) in dichloromethane (6 ml) is added dropwise, at 0° C. while stirring, to a mixture of 3-methoxymethyl-1-(3,4,5trimethoxybenzyl)piperazine (0.4 g) obtained in Reference Example 14, triethylamine (0.3 g) and dichloromethane (6 ml). After stirring at room temperature for one hour, the reaction mixture is added to water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=2:2:1) to afford 1-(2,3-dimethoxy-6,7-dihydro-5H-benzo-cyclohepten-8-ylcarbonyl) -2-methoxymethyl-4-(3,4,5-tri-methoxybenzyl)piperazine (0.6 g) as a colorless oily product. This product is converted to the hydrochloride, and treated with ethyl ether to give pale yellow powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:9](Cl)(=O)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].SC1C=C(C=CC=1)C(O)=O>>[SH:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2]
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C(O)c1cccc(S)c1
Product: N#Cc1cccc(S)c1

Procedure:
The required 3-Mercapto-benzonitrile is prepared from 3-Cyano-benzenesulfonyl chloride following the procedure for the preparation of 3-Mercaptobenzoic acid described in Journal of Heterocyclic Chemistry (1982), 19(4), 961-5.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[H-].[Na+].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:22]=[CH:23]/[CH:24]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([O:46][CH3:47])=[O:45])=[CH:40][CH:39]=1)[CH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.[Cl-].[NH4+]>CN(C=O)C>[CH3:47][O:46][C:44]([C:41]1[CH:40]=[CH:39][C:38]([CH2:37][CH:24](/[CH:23]=[CH:22]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:3]2[CH2:4][CH2:5][O:1][C:2]2=[O:6])[CH2:25][CH2:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=2)=[CH:43][CH:42]=1)=[O:45]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCCl)Cc2ccc(C(=O)OC)cc2)cc1
Reactant: O=C1NCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCCCN2CCOC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 16.7 mg (0.19 mmol) of 2-oxazolidinone [CAS Reg. No. 497-25-6] is initially charged in 1.0 ml of dry DMF, and 7.9 mg (0.196 mmol) of sodium hydride (60% in paraffin oil) are added. The mixture is stirred at room temperature for 45 min. The reaction solution is then cooled to 0° C. and a solution of 30 mg (0.055 mmol) of methyl 4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate (racemate; Example 32A) in 0.5 ml of dry DMF is added. The mixture is stirred at room temperature for 1.5 h. The reaction solution is then carefully poured into 5 ml of ice-cold 10% strength ammonium chloride solution. The mixture is extracted twice with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated. This gives 25 mg (0.042 mmol, 76% of theory) of a colorless oil which is reacted without further purification.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C@@H:5]([OH:15])[CH2:6][P:7]([CH3:14])(=[O:13])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COP(C)(=O)C[C@H](O)CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)COP(C)(=O)C[C@H](O)CN

Procedure:
To a solution of 2.2 g of isobutyl P-[3-azido-2(R)-hydroxy-propyl]-P-methyl-phosphinate in 25 ml of ethanol is added 0.25 g of 5% palladium on charcoal. The resulting mixture is hydrogenated at 1 bar until hydrogen uptake ceases. The mixture is then filtered and the filtrate evaporated to give isobutyl P-[3-amino-2(R)-hydroxy-propyl]-P-methyl-phosphinate as a viscous oil, 31P-NMR spectrum: δ=+55.6 and +54.6 ppm (CDCl3), [α]D25 =-9.9 (0.66% in ethanol).
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]([NH:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].O.[OH-].[Li+]>O1CCCC1.O>[F:22][C:20]([F:21])([F:23])[C:15]1[CH:14]=[C:13]([NH:12][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])[C:3]([OH:24])=[O:2])[CH:18]=[C:17]([F:19])[CH:16]=1
Reactant: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCCC(Nc1cc(F)cc(C(F)(F)F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
2-(3-Trifluoromethyl-5-fluoro-phenylamino)-non-8-enoic acid methyl ester (1.643 g, 4.73 mmol., 1 eq.) was dissolved in tetrahydrofuran (40 mL). A solution of lithium hydroxide monohydrate (0.596 g, 14.19 mmol., 3 eq.) in water (40 mL) was added dropwise and the reaction mixture stirred for a further 3 hours at ambient temperature by when LCMS analysis of an aliquot showed the reaction to be complete. The reaction mixture volume was reduced by half in vacuo to remove most of the tetrahydrofuran and the obtained solution was diluted with 1.5M hydrochloric acid (40 mL). The solution was extracted with dichloromethane (2×60 mL). The organic extracted were combined, dried over sodium sulfate and the solvent removed in vacuo to give 1.41 g (90%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3) δ ppm 6.68 (d, J=8.54 Hz, 1 H), 6.63 (s, 1 H), 6.44 (dd, J=1.98, 10.68 Hz, 1 H), 5.72-5.85 (m, J=6.64, 6.64, 10.28, 17.03 Hz, 1 H), 5.00 (dq, J=1.66, 17.15 Hz, 1 H), 4.95 (dt, J=0.97, 10.11 Hz, 1 H), 4.07 (dd, J=5.80, 6.87 Hz, 1 H), 2.19 (s, 2 H), 2.05 (q, J=6.87 Hz, 2 H), 1.90-1.99 (m, 1 H), 1.74-1.86 (m, 1 H), 1.43-1.51 (m, 2 H), 1.32-1.43 (m, 3 H). LC-MS: purity 98% (UV), tR 2.33 min, m/z [M+H]+334.10
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:1][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)[CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc2ccc(-c3nnn(C)n3)cc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nnc(-c2ccc3scc(CBr)c3c2)n1
Yield: 74.1 %

Procedure:
To a refluxing mixture of 3-methyl-5-(2-methyltetrazol-5-yl) benzo[b]thiophene (0.162 g, 0.703 mmol) and benzoyl peroxide (10.6 mg) in carbon tetrachloride (10 ml) irradiated with two desk lamps (2×60W) was added N-bromosuccinimide (0.126 g, 0.707 mmol) in small portions. After the addition was complete the mixture was heated at reflux for a further 90 min, then filtered and the filtrate was evaporated in vacuo to leave an oil/solid mixture. Chromatography on flash silica, eluting with dichloromethane gave 0.161 g of crude 3-bromomethyl-5-(2-methyltetrazol-5-yl) benzo[b]thiophene as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[N:11][NH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2cnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2cn[nH]c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81 %

Procedure:
A suspension of 4-(4-fluorophenyl)-1-trityl-1H-pyrazole (0.370 g) was suspended in a mixture solution of trifluoroacetic acid (5 ml)/methylene chloride (10 ml) and stirred for 10 min at room temperature, followed by irradiating microwaves thereto at 70° C. for 20 min to induce a reaction. After the reaction was terminated, the solution was diluted in methylene chloride (20 ml), neutralized with 1N sodium hydroxide (20 ml), and washed with distilled water (30 ml) and then with brine (20 ml). The washed organic layer thus formed was dried over anhydrous magnesium sulfate and concentrated by evaporation in a vacuum. The residue thus obtained was separated using silica gel chromatography to give 4-(4-fluorophenyl)-1H-pyrazole (Yield 81%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:32][C:33]3[CH:39]=[C:38]([C:40]([O-])=[O:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:27][CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:32][C:33]3[CH:39]=[C:38]([C:40]([NH:22][C:20]4[CH:19]=[CH:18][C:16]5[NH:17][C:13]([C:10]6[CH:11]=[CH:12][C:7]([N:4]7[CH2:5][CH2:6][O:1][CH2:2][CH2:3]7)=[CH:8][CH:9]=6)=[N:14][C:15]=5[CH:21]=4)=[O:41])[CH:37]=[CH:36][C:34]=3[N:35]=2)=[CH:29][CH:30]=1)#[N:24]
Reactant: Nc1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Reactant: N#Cc1ccc(-c2nc3ccc(C(=O)[O-])cc3[nH]2)cc1
Product: N#Cc1ccc(-c2nc3ccc(C(=O)Nc4ccc5[nH]c(-c6ccc(N7CCOCC7)cc6)nc5c4)cc3[nH]2)cc1

Procedure:
Compound 292 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinophenyl)-5-aminobenzimidazole and 2-(4-cyanophenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C32H25N7O2: 540.21; found: 539.97.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][N:5]1[CH2:29][CH2:28][C:8]2([N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=[C:9]2[NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:7][CH2:6]1.Br[CH2:35][CH2:36][CH2:37][C:38]#[N:39].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH:22]1([NH:21][C:9]2[C:8]3([CH2:28][CH2:29][N:5]([CH2:4][C:3]4[CH:30]=[CH:31][CH:32]=[CH:33][C:2]=4[NH:1][CH2:35][CH2:36][CH2:37][C:38]#[N:39])[CH2:6][CH2:7]3)[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:11](=[O:20])[N:10]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: N#CCCCBr
Reactant: Nc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: N#CCCCNc1ccccc1CN1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1cccc(F)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A 2 mL CH3CN suspension of 0.05 g (0.11 mmol) 8-(2-aminobenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one (example 80), excess 4-bromobutyronitrile and Cs2CO3 was heated to 60° C. and allowed to stir for 2 days. HPLC/MS showed a small amount of product so the reaction was filtered and concentrated. The remaining oil was purified on an Isco automated system affixed with a Biotage Flash 25(M) cartridge eluted with 0-5% MeOH+0.5M NH3 in CH2Cl2 over 30 min at 20 mL/min. The product eluted last.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24]#[N:25])[C:18]=2[CH2:17][CH2:16][NH:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:15]3[CH2:16][CH2:17][C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][C:23]=4[CH2:14]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: N#Cc1cccc2c1CCNC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: N#Cc1cccc2c1CCN(C(=O)c1cc3ncc(Br)cn3n1)C2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1,2,3,4-Tetrahydro-isoquinoline-5-carbonitrile to provide the title compound in moderate yield.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH2:19]2)=[C:15]([F:22])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:22][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:20]3[C:21]=2[C:16]=1[CH2:17][CH2:18][CH2:19]3
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)c3c2n1CCC3
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)c3c2n1CCC3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
To an ice-cooled solution of [(S)-1-(7-fluoro-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethyl]carbamic acid tert-butyl ester (78 mg, 0.244 mmol) in DCM (4 mL) was added TFA (1.3 mL) and the mixture was stirred at RT for 1.5 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a colourless gum (49.5 mg, 93%). LCMS (Method B): RT 1.78 min [M+H]+ 220
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC(=O)NC1(CCC2C=CC(S(N3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)(=O)=O)=CC=2)COC(C)(C)OC1)(C)(C)C>>[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=2)[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: COc1cc(CCc2cccc(CCC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)c2)cc(OC)c1OC
Agent: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(S(=O)(=O)c3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Product: COc1cc(CCc2cccc(CCC(N)(CO)CO)c2)cc(OC)c1OC
Yield: 74 %

Procedure:
When the product of Step C was substituted for tert-butyl-5-(4-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-ylsulfonyl)-phenethyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 13, Step F, the similar process afforded the title compound in 74% yield, as colourless solid. 1H-NMR (CDCl3) 1.7-1.8 (m, 2H); 2.51-2.52 (m, 2H); 2.77 (s, 4H); 3.31-3.42 (m, 13H); 6.26 (s, 2H); 6.81 (s, 1H); 6.95-6.97 (m, 2H); 7.13 (tr, 1H, J=7.44 Hz).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.[F:16][C:17]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[CH:19][C:18]=1[C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[N:36][CH:37]=1>>[NH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=2[C:21]2[CH:20]=[CH:19][C:18]([C:32]3[CH:37]=[N:36][C:35]([NH2:38])=[N:34][CH:33]=3)=[C:17]([F:16])[CH:22]=2)=[N:10][CH:9]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: Nc1ccc(Oc2ccccc2Br)nc1
Product: Nc1ccc(Oc2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)nc1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 6-(2-bromophenoxy)pyridin-3-amine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H16FN5O, 373.14; m/z found, 373.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 7.53 (m, 1H), 7.50-7.45 (m, 2H), 7.44-7.38 (m, 2H), 7.36-7.30 (m, 1H), 7.20 (t, J=7.4, 1H), 7.06-7.00 (m, 1H), 6.91 (d, J=8.0, 1H), 6.85 (s, 2H), 6.72 (d, J=8.6, 1H), 5.03 (s, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].[NH2:9][OH:10]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](=[N:9][OH:10])[NH2:8]
Reactant: NO
Reactant: N#CCc1cccs1
Product: NC(Cc1cccs1)=NO
Reaction time: 8 h

Procedure:
290 g. (2.35 moles) of 2-thienylacetonitrile is treated with the equivalent amount of alcoholic hydroxylamine solution and stirred overnight to obtain 2-thienylacetamidoxime. By concentrating, treating the residue with anhydrous chloroform, filtering and again concentrating, the crude amidoxime is obtained in the form of a syrup. The syrupy residue is dissolved in 1000 ml. of anhydrous dioxane and the cooled solution is treated dropwise first with 854 g. of trichloroacetyl chloride then with 380 ml. of pyridine. The mixture is then stirred overnight at room temperature. The dioxane is distilled off in a rotary evaporator and the residue is added to a liter of water. The oily substance which separates is treated with ether. The ether solution is repeatedly washed with water, neutralized with saturated sodium bicarbonate solution, washed several times with water and dried with magnesium sulfate. After concentrating, the residue is treated with 750 ml. of toluene and refluxed in a reflux condensor for about 2 hours. A small amount of water is removed. The toluene solution is treated with activated carbon, filtered, concentrated and the residue is distilled under vacuum. 258 g. of 3-(2-thienylmethyl)-5-(trichloromethyl)-1,2,4-oxadiazole are obtained, b.p. 0.01 119°-122°.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[CH:17][N:16]=[C:15]([NH2:21])[C:14]=2[N:13]=[C:12]1[CH2:22][O:23][CH2:24][CH3:25].C(N(CC)CC)C.C(Cl)(Cl)Cl>[OH-].[Na+]>[NH2:21][C:15]1[C:14]2[N:13]=[C:12]([CH2:22][O:23][CH2:24][CH3:25])[N:11]([CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:19]=2[C:18]([CH3:20])=[CH:17][N:16]=1
Reactant: CCOCc1nc2c(N)ncc(C)c2n1CCCCN
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)ncc(C)c2n1CCCCNS(C)(=O)=O

Procedure:
Methanesulfonyl chloride (4 eq) was added dropwise to a mixture of 1-(4-aminobutyl)-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-4-amine (2.25 g, 8.11 mmol), triethylamine (10.2 mL, 73.0 mmol) and chloroform (225 mL). The solvent was removed under reduced pressure to provide an oil. The oil was dissolved in 10% sodium hydroxide (200 mL) then extracted with chloroform (3×300 mL). The combined extracts were dried over magnesium sulfate and then concentrated under reduced pressure to provide a clear oil. The oil was purified by column chromatography (silica gel eluting with 90/10 dichloromethane/methanol) to provide a white solid. This material was dried overnight under vacuum at 80° C. to provide 0.71 g of N-{4-[4-amino-2-(ethoxymethyl)-7-methyl-1H-imidazo[4,5-c]pyridin-1-yl]butyl}methanesulfonamide as a white solid, m.p. 173-175° C.