Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]([CH3:12])[CH3:11])[S:7][CH:8]=1.Cl.[NH2:14][CH2:15][CH2:16][SH:17].O.[OH-].[Na+]>ClCCl>[NH2:14][CH2:15][CH2:16][S:17][CH2:3][C:4]1[N:5]=[C:6]([CH2:9][N:10]([CH3:12])[CH3:11])[S:7][CH:8]=1
Reactant: CN(C)Cc1nc(CCl)cs1
Reactant: NCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1nc(CSCCN)cs1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the aqueous phase from Example 14 above was added 27 g. of 2-aminoethanethiol, hydrochloride. The mixture was heated and stirred, until the pot temperature reached 120°. The mixture was held at that temperature for 6 hours, and was then allowed to cool to 60°. To the residue was added 80 ml. of deionized water, and the mixture was allowed to cool to ambient temperature and stand for some days. Eighty ml. of dichloromethane was then added, and the pH of the mixture was adjusted to 6.1 by the addition of 9 ml. of 50% sodium hydroxide. The aqueous layer was extracted twice with 40 ml. portions of dichloromethane, and the aqueous layer was then mixed with 80 ml. of dichloromethane and the pH was adjusted to 12.6 by the addition of 40 ml. of 50% sodium hydroxide. The aqueous layer of the resulting mixture was extracted twice with 40 ml. of dichloromethane, and the two aqueous layers were combined, filtered and evaporated under vacuum to obtain 31.5 g. of the desired product, which was found to be 74.7% pure by the analytical method described in Preparation 1 above.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C@@H:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:19])[C@@H:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](Nc1ccccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H](Nc1ccccc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.8 %

Procedure:
To a solution of (S)-2-(2-Nitro-phenylamino)-propionic acid tert-butyl ester (1.6 g, 6.0 mmol) in MeOH (20 mL) was added a slurry of 10% Pd/C (dry) (300 mg). The reaction mixture was degasses using house vacuum aspirator and then saturated with H2 gas in balloon. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then filtered through a celite and the filtrate was concentrated to afford 1.5 g (100%) of the desired product as a dark brown oily residue. This product was used for the next reaction without purification.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:14]2[C:9](=[CH:10][C:11]([F:16])=[C:12](Cl)[CH:13]=2)[C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6]1)([CH3:4])[CH3:3].[CH3:21][C:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>CN1CCCC1=O>[CH3:21][C:22]([N:25]1[CH2:30][CH2:29][N:28]([C:12]2[CH:13]=[C:14]3[C:9]([C:8](=[O:17])[C:7]([C:18]([OH:20])=[O:19])=[CH:6][N:5]3[C:2]([CH3:4])([CH3:3])[CH3:1])=[CH:10][C:11]=2[F:16])[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)N1CCNCC1
Reactant: CC(C)(C)n1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: CN1CCCC1=O
Product: CC(C)(C)N1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C(C)(C)C)CC1
Temperature: 100 °C
Yield: 22.3 %

Procedure:
A mixture of 0.45 g (1.51 mmoles) 1-(1,1-dimethylethyl)-1,4-dihydro-7-chloro-6-fluoro-4-oxo-3-quinolinecarboxylic acid and 0.65 g (4,56 mmoles) 1-(1,1-dimethylethyl)piperazine in 2 mL N-methylpyrrolidone were heated 5 hours at 100° C. The solvent was evaporated under reduced pressure. The residue was tritured in water. The precipitate was recrystallized in ethanol to give 0.136 g of titled compound. MP>270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[CH:17][N:16]=1>C1COCC1.O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[Cl:1])=[CH:17][N:16]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)nc2)c(Cl)c1

Procedure:
2-Chloro-4-nitrophenol (17.4 mmol) in 15 ml of THF is slowly added to a stirring suspension of sodium hydride (17.4 mmol) in 25 ml of THF. After gas evolution has ceased, 2-chloro-5-bromomethylpyridine is added and the mixture is heated under reflux overnight. The reaction is diluted with water, extracted with chloroform, washed with water, dried and stripped to give 2-chloro-5-(2-chloro-4-nitrophenoxy)methylpyridine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[CH2:11](Br)[C:12]#[CH:13].C1(C)C=CC=CC=1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+].O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:13][C:12]#[CH:11])[NH2:10])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: C#CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: C#CCN(N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48 %

Procedure:
4-Chlorophenylhydrazine hydrochloride (550 mg, 3 mmol) was added to a vigorously stirred mixture of tetra-n-butylammonium chloride (42 mg, 0.15 mmol) in 50% aqueous sodium hydroxide (3 mL) followed by 80% propargyl bromide in toluene (490 mg, 3.3 mmol). The reaction was stirred at room temperature for 20 h. The reaction was diluted with water (30 mL) and extracted with chloroform (3×10 mL). The combined organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to a dark brown oil (530 mg). The oil was subjected to column chromatography (silica gel, eluent: 50% dichloromethane in hexanes) to give an orange solid (260 mg, 48%).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:26]([CH:27]([CH3:29])[CH3:28])[N:25]=[CH:24][N:23]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH:27]([N:26]1[C:22]([C:17]2[N:18]=[C:19]3[C:20]4[CH:21]=[C:8]([CH:6]([N:34]5[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]5)[CH3:7])[CH:9]=[CH:10][C:11]=4[O:12][CH2:13][CH2:14][N:15]3[CH:16]=2)=[N:23][CH:24]=[N:25]1)([CH3:28])[CH3:29]
Reactant: CN1CCNCC1
Reactant: CC(OS(C)(=O)=O)c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Product: CC(c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)cn1CCO2)N1CCN(C)CC1
Temperature: 90 °C

Procedure:
A mixture of 1-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (246 mg, 0.590 mmol) in 1-methylpiperazine (25 mL) was heated at 90° C. for 16 h. The solvent was removed and the residue was purified by Combi-flash eluting with a 5-95% gradient of CH3CN in 0.3% NH4HCO3 to give 146. Separation of the enantiomers and further purification by chiral HPLC (AY-H column, 5% EtOH isocratic) gave: 44.3 mg of one enantiomer and 40.0 mg of the other (34% total yield).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:25])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[H][H]>[Pt].C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH3:25])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Reactant: [H][H]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)ccc21
Yield: 89.1 %

Procedure:
A mixture of 0.50 g of N-(4-chlorobenzyl)-6-(3-hydroxy-1-propynyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Example No. 31 and 50 mg of 5% platinum on carbon catalyst in 20 mL of 1:1 THF-methanol is stirred under 1 atm hydrogen for 3 h, then filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure and the residual solid flash chromatographed on silica gel using 4-5% methanol in dichloromethane to afford 0.45 g of the title compound as a yellow solid. Further purification is achieved by recrystallization of the solid from 15 mL of acetonitrile.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.[CH3:8][N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][NH:12]2.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(Cl)Cl>[CH3:8][N:9]1[CH2:14][C@@H:13]2[CH2:15][C@H:10]1[CH2:11][N:12]2[C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1
Reactant: Cc1nsc(Cl)n1
Reactant: CN1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1nsc(N2C[C@@H]3C[C@H]2CN3C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.2 %

Procedure:
A solution of 1.04 g of 5-chloro-3-methyl-1,2,4-thiadiazole, prepared by the procedure of J. Goerdeler, Chim. Ber., 1957, 90, 182, in 2 ml of tetrahydrofuran is added over one hour to a solution of 0.825 g of (S,S)-2-methyl-2,5-diazabicyclo[2.2.1]heptane and 0.77 g of potassium carbonate in 10 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature overnight, diluted with methylene chloride and the organic layer is washed with water. The methylene chloride solution is dried and concentrated in vacuo to dryness. The residue is purified by chromatography (aluminum oxide, Activity Grade 2.5: 2% methyl alcohol/methylene chloride) to give 0.56 g of the desired product:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:10][Mg]Br.CCOCC>C1COCC1>[OH:9][CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)[CH3:10]
Reactant: Cc1cccc(C=O)n1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cccc(C(C)O)n1
Reaction time: 1 h

Procedure:
To 6-methylpyridine-2-carboxaldehyde (2.0 g, 16.5 mmol) in dry THF (55 mL) at 0° C. under nitrogen, add a solution of 3M methyl magnesium bromide in ether (6.0 mL, 18.0 mmol,) dropwise with stirring. After 1 h at 0° C., quench with saturated aqueous NH4Cl, extract three times with EtOAc, dry over anhydrous Na2SO4 and concentrate in vacuo to give the desired intermediate (crude, 2.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:26]Cl)=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)=[CH:9][C:8]([O:22][CH3:23])=[C:7]([O:24][CH3:25])[CH:6]=2.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>ClCCl>[Cl:1][C:2]1[C:3]([CH2:26][N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])=[N:4][C:17]2[C:12]([C:11]=1[C:10]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([O:22][CH3:23])[CH:9]=1)=[CH:13][C:14]([O:20][CH3:21])=[C:15]([O:18][CH3:19])[CH:16]=2
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3cc(OC)c(OC)cc23)cc1OC
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)Cc1nc2cc(OC)c(OC)cc2c(-c2ccc(OC)c(OC)c2)c1Cl
Yield: 67.4 %

Procedure:
A mixture of 3-chloro-2-chloromethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (2.0 g), diethylamine (2.5 g) and dichloromethane (50 ml) was stirred under reflux for 14 hours. The reaction mixture was washed with water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography on silica gel. The fractions eluted with chloroform gave 3-chloro-2-(N,N-diethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline (1.47 g, 67%). This compound was recrystallized from ethyl acetate-hexane to give colorless prisms, mp. 146°-148° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:27])=O>ClCCl.CN(C)C=O>[Cl:27][C:19]([C:18]1[CH:22]=[CH:23][C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1
Temperature: 25 °C

Procedure:
0.330 g of trans-4-(4-tert-butoxycarbonylmethylcyclohexyl)benzoic acid is placed in 10 mL of dichloromethane with stirring, at room temperature, under a nitrogen atmosphere. 0.12 mL of oxalyl chloride (1.42 mmol, 1.4 eq.) and 2 drops of dimethylformamide are successively added. The reaction medium is stirred for 2 hours and concentrated under vacuum. The tert-butyl trans-4-(4-chlorocarbonylphenyl)cyclohexaneacetate formed is dissolved in 8 mL of acetonitrile and placed under nitrogen. The mixture is cooled in an ice bath and 0.17 g of potassium thiocyanate (1.75 mmol, 1.7 eq.) is added. The reaction mixture is stirred at room temperature for 1 hour 30 minutes. 0.380 g of cyclopentyloxyacetic acid hydrazide (2.40 mmol, 2.32 eq.) dissolved in 5 mL of acetonitrile is then added and the mixture is refluxed for 2 hours 30 minutes and then left to stand at room temperature for 36 hours. The precipitate formed is filtered off and washed with acetonitrile. The filtrate is diluted with dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated under vacuum. The residue is dissolved in 5 mL of dichloromethane; 3 mL of trifluoroacetic acid are added and the reaction medium is stirred for 1 hour 30 minutes and concentrated under vacuum. After triturating in methanol, ethanol and ethyl acetate, the residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 3% to 5%. After triturating in ethanol, 0.070 g of trans-{4-[4-(5-cyclopentyloxymethyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]cyclohexyl}acetic acid is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([CH3:21])[N:18]([NH2:20])[CH:19]=1.C(O)(=O)C.[CH:26](N)=[NH:27]>CC(O)CC>[Br:8][C:9]1[N:13]([CH3:14])[N:12]=[CH:11][C:10]=1[C:15]1[N:16]=[C:17]([CH3:21])[N:18]([NH:20][CH:26]=[NH:27])[CH:19]=1
Reactant: N=CN
Reactant: Cc1nc(-c2cnn(C)c2Br)cn1N
Solvent: CC(=O)O
Solvent: CCC(C)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(-c2cnn(C)c2Br)cn1NC=N
Temperature: 100 °C
Reaction time: 18 h

Procedure:
4-(5-Bromo-1-methyl-1H-pyrazol-4-yl)-2-methyl-1H-imidazol-1-amine, trifluoroacetate salt (4.90 g, 113.2 mmol) was combined with formamidine acetate (98%, 4.92 g, 46.3 mmol) in 2-butanol (40 mL), and the reaction mixture was heated at 100° C. for 6 hours, then allowed to cool to room temperature and stir for 18 hours. The off-white solid was collected by filtration and washed with 2-propanol followed by diethyl ether. The solid was then triturated with aqueous ammonium hydroxide (7.5 M, 40 mL); filtration provided a white solid, which was washed with 2-propanol followed by diethyl ether to provide the product. Yield: 2.70 g, 9.54 mmol, 72%. 1H NMR (500 MHz, CD3OD), presumed to be a mixture of rotamers or tautomers: δ 2.26 and 2.31 (2 s, 3H), 3.89 and 3.89 (2 s, 3H), 7.26 and 7.40 (2 s, 1H), 7.41 and 7.96 (2 br s, 1H), 7.85 and 7.82 (2 s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][CH:18]([CH3:24])[C:17]=2[CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:30]=[C:31]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][CH:18]([CH3:24])[C:17]=3[CH:25]=2)=[CH:10][CH:11]=[C:12]1[C:31]#[N:30])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC1OCC(=O)Nc2ccc(-c3cccn3C(=O)OC(C)(C)C)cc21
Product: CC1OCC(=O)Nc2ccc(-c3ccc(C#N)n3C(=O)OC(C)(C)C)cc21

Procedure:
tert-Butyl-2-cyano-5-(5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-(5-methyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.30 (s, 1H), 7.37-7.25 (m, 3H), 7.16 (d, J=8.26 Hz, 1H), 6.46 (d, J=3.77 Hz, 1H), 4.81 (q, J=6.14 Hz, 1H), 4.47 (d, J=16.42 Hz, 1H), 4.36 (d, J=16.44 Hz, 1H), 1.51 (d, J=6.48 Hz, 3H), 1.37 (s, 9H); MS (ES) m/z 366 ([M−H]−, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:12]([CH2:14][C:15]([OH:17])=[O:16])#[N:13].C([O-])(=O)C.[NH4+].C1C=CC=CC=1>N1C=CC=CC=1.Cl>[C:12]([C:14](=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)[C:15]([OH:17])=[O:16])#[N:13]
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: N#CCC(=O)O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: N#CC(=Cc1ccc2c(c1)CCO2)C(=O)O

Procedure:
39.5 g of 2,3-dihydro-5-benzofurancarbaldehyde (prepared according to the process described in J. Org. Chem. (1984), 49, p. 409), 22.7 g of 2-cyanoacetic acid and 4.08 g of ammonium acetate are mixed in 37 ml of pyridine and 210 ml of benzene The mixture is brought to reflux for 6 hours 30 minutes. The precipitate formed is isolated and then suspended in 600 ml of 6 N hydrochloric acid. The solid isolated is filtered off and washed with water and dried in the air.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14](=[O:16])[CH3:15])[CH2:4][CH:3]1[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])=[O:28].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:30]1([CH3:35])[C:29]([C:27]([CH2:26][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14](=[O:16])[CH3:15])[CH2:4][CH:3]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:2]2=[O:1])=[O:28])=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)c2ccccc2C)c2cc(C)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-acetyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.30 g) was suspended in toluene (18 ml), 2-bromo-2′-methylacetophenone (1.00 g), 1N aqueous sodium hydroxide (9 ml) and tetra n-butylammonium bromide (20 mg) were added thereto, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was weakly acidified with 1N hydrochloric acid, extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 1.45 g of the titled compound (Yield: 79.7%).
Reaction SMILES: I[C:2]1[O:3][C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[CH3:16])=[CH:5][N:6]=1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=1.CN1C(=O)CCC1.CO>C(Cl)Cl>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:2]2[O:3][C:4]([C:7]3[CH:8]=[C:9]4[C:13](=[CH:14][CH:15]=3)[NH:12][N:11]=[C:10]4[CH3:16])=[CH:5][N:6]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1n[nH]c2ccc(-c3cnc(I)o3)cc12
Solvent: CN1CCCC1=O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(-c3ccc4[nH]nc(C)c4c3)o2)cc1
Temperature: 165 °C
Yield: 1026.1 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2-iodooxazol-5-yl)-3-methyl-1H-indazole (0.40 g, 123 μmol), (4-methoxyphenyl)methanamine (1.13 mL, 8620 μmol) and NMP (2.0 mL). The reaction mixture was stirred and heated in a Smith Synthesizer® microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 165° C. for 10 minutes. The crude product was adsorbed onto a plug of silica gel and chromatographed through two stacked Redi-Sep® pre-packed silica gel column (12 g), eluting with a gradient of 1% to 10% 2 M NH3.MeOH in DCM, to give N-(4-methoxybenzyl)-5-(3-methyl-1H-indazol-5-yl)oxazol-2-amine (422 mg, 98% yield). LCMS (API-ES) m/z (%): 355 (100%, M++H); 1H NMR (400 MHz, MeOH-d4) 7.76 (s, 1H) 7.52 (s, 1H) 7.48-7.57 (m, 1H) 7.38-7.46 (m, 1H) 7.26-7.34 (m, 2H) 6.96-7.02 (m, 1H) 6.80-6.91 (m, 2H) 4.42 (s, 2H) 3.75 (d, J=6.06 Hz, 3H) 3.30 (s, 3H).
Reaction SMILES: C(OC([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10](Br)=[CH:9]1)=O)(C)(C)C.O1CCCC1.[CH3:23][O:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:8][CH:9]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC(C)(C)OC(=O)n1cc(Br)c2cccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1OC

Procedure:
Into a round bottom flask was added 3-Bromo-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (6, 2.8 g, 9.4 mmol) and tetrahydrofuran (100 mL). Tetrakis(triphenylphosphine)palladium(0) (500 mg, 0.50 mmol), 3,4-dimethoxyphenylboronic acid (2.1 g, 11 mmol) and 1 M K2CO3 solution (50 mL) The reaction mixture was stirred at 65° C. overnight. The reaction mixture was poured into water and extracted into ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The crude material was purified by column chromatography (gradient system of hexanes and ethyl acetate) to yield the titled compound, 1, (500 mg, 2 mmol, 20%) and 3-(3,4-dimethoxy-phenyl)-pyrrolo[2,4-b]pyridine-1-carboxylic acid tert-butyl ester (2.1 g, 5.9 mmol, 63%). The later compound can be easily converted to the desired compound, 1 by treatment with acid reagents such as TFA or HCl.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([N:12]1[CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:25])[CH:20]=3)[NH:15][C:14]=2[CH:13]1[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)=[O:11])=O)(C)(C)C.[ClH:33].O1CCOCC1>>[NH2:8][CH2:9][C:10]([N:12]1[CH2:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH3:25])[CH:20]=3)[NH:15][C:14]=2[CH:13]1[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1)=[O:11].[ClH:33]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CNC(=O)OC(C)(C)C)C3c1cccc(O)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c3c(c2c1)CCN(C(=O)CN)C3c1cccc(O)c1

Procedure:
(tert-Butoxy)-N-{2-[1-(3-hydroxyphenyl)-6-methyl-(1,2,3,4-tetrahydro-beta-carbolin-2-yl)]-2-oxoethyl}carboxamide 11 was treated with HCl in dioxane (4 N, 10 equiv) for 30 min, and the solvent was removed to give 3-(2-glycyl-6-methyl-2,3,4,9-tetrahydro-1H-beta-carbolin-1-yl)phenol 14 as its HCl salt.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=4)=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=1.[C:36]([Cu])#[N:37]>CN(C=O)C>[C:36]([C:2]1[CH:3]=[CH:4][C:5](=[O:35])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:15][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=4)=[O:20])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1)#[N:37]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3cc(I)ccc3=O)CC2)C1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: N#Cc1ccc(=O)n(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
A solution of N-({1-[4-(5-iodo-2-oxo-2H-pyridin-1-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (as prepared in Example 8, Step C, 300 mg, 0.5 mmol), CuCN (Aldrich, 1 mmol), DMF (4 mL) in a sealed tube was irradiated under microwave at 180° C. for 30 min. The solid was filtered off and the residue was partitioned between water and a chloroform/IPA “cocktail” (˜3:1, v/v). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give the crude product, which was then purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the title compound as yellow solid.