Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]=O>CC(O)=O.CC(N(C)C)=O>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH3:20])[CH:17]=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1cccc(Nc2nccc(-c3ccc(N)s3)n2)c1
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(Nc2nccc(-c3ccc(NCc4ccccn4)s3)n2)c1
Reaction time: 18 h

Procedure:
A solution of [4-(5-aminothiophen-2-yl)-pyrimidin-2-yl]-m-tolyl-amine (prepared according to Method 4) (15 mg, 0.053 mmol) and pyridine-2-carbaldehyde (4.5 uL, 0.048 mmol) were dissolved in a 25% solution of HOAc in DMA (0.5 mL). MP-CNBH3 resin (2.5 eq.) was added after 2 h and the reaction was shaken for 18 h. The reaction was filtered and the resin washed with DMA. The crude mixture was purified by preparative LCMS to afford 11.1 mg, 61.2%). MS: m/z 374 (M+H+). 1H NMR (500 MHz, DMSO-d6) δ 2.26 (s, 3H), 4.42 (d, J=6.5 Hz, 2H), 5.96 (d, J=4.5 Hz, 1H), 6.72 (d, J=7.5 Hz, 1H), 6.986 (d, J=5.5 Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 7.27 (m, 1H), 7.38 (d, J=7.5 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.56 (d, J=4.0 Hz, 1H), 7.73 (br s, 1H), 7.76 (m, 1H), 7.81 (t, J=5.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.53 (br dd, J=4.5 Hz, 1H), 9.24 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]#[N:29])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH2:27][C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4CC#N)ccc3o2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1csc(-c2cc3cc(OCc4ccccc4Cc4nnn[nH]4)ccc3o2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(2-cyanomethylphenylmethoxy)benzofuran-2-yl]thiazole (0.40 g), sodium azide (0.58 g) and ammonium chloride (0.66 g) in N,N-dimethylformamide (4 ml) was stirred at 110° C. for 8 hours. After being cooled, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with chloroform, successively with a mixture of chloroform and methanol (10:1). The fractions containing object compound were combined and concentrated under reduced pressure to give 5-{2-(2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxymethyl]phenylmethyl}-1H-tetrazole (0.21 g).
Reaction SMILES: [CH3:1][C:2]12[CH:17]([CH3:18])[CH:15]3[NH:16][C:11]4[CH:12]([CH2:14]3)[CH2:13][C:4](=[C:5]([CH:10]=4)[CH:6]=[CH:7][CH2:8][NH:9]1)[CH2:3]2.CN(C)C=O.C(N(C(C)C)CC)(C)C.[CH:33]1([CH2:36]Br)[CH2:35][CH2:34]1>O.C(OCC)(=O)C>[CH:33]1([CH2:36][CH:14]2[CH:12]3[CH2:13][C:4]4[CH2:3][C:2]5([CH3:1])[CH:17]([CH3:18])[CH:15]2[NH:16][C:11]3=[CH:10][C:5]=4[CH:6]=[CH:7][CH2:8][NH:9]5)[CH2:35][CH2:34]1
Reactant: CC1C2CC3CC4=C(C=CCNC1(C)C4)C=C3N2
Reactant: BrCC1CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1C2NC3=CC4=C(CC3C2CC2CC2)CC1(C)NCC=C4
Temperature: 25 °C
Yield: 23 %

Procedure:
To a stirred solution of 0.99 g of 6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-8H-pyrrolo[2,3-i][3]benzazocine and 18 ml of dimethylformamide was added 1.44 ml of diisopropylethyl amine. Cyclopropylmethyl bromide (0.48 ml) was added, under nitrogen, and the reaction mixture was heated at 82°-83° C. for 6 hr. The reaction mixture was cooled to room temperature and was poured into ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate and ether. The combined organic layers were washed with water and brine, dried over anhydrous potassium carbonate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 2% triethylamine/0-15% methanol/ethyl acetate), a second column (silica gel, 2% triethylamine/ethyl acetate), and a third column (silica gel, 1% triethylamine/ether) to afford 0.28 g (23%) of the product, as an oil, which crystallized upon trituration with ether. Recrystallization from ether-pentane gave the analytical sample, mp 164°-166° C.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[Br:12][CH2:13][CH2:14][CH2:15]Br.CN(C)C=O>O>[Br:12][CH2:13][CH2:14][CH2:15][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: BrCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCn1ccc2ccccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
9.58 g of potassium hydroxide (KOH) and 20.00 g of indole were added to 110.58 g of 1,3-dibromopropane and 450 mL of N,N-dimethylformamide (DMF), and the mixture was stirred at 70° C. for 8 hours. After cooling to room temperature, 1 L of distilled water was added to the reaction solution, and the resulting solution was extracted with 1 L of ethyl acetate. The organic layer was washed with 500 mL of distilled water five times, then concentrated and purified by column chromatography to obtain 27.24 g of N-(3-bromopropyl)-indole. Compounds (p-9) and (p-10) having a bromopropyl group shown below were also synthesized in the same manner.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[Cl:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: Nc1cccc(Cl)c1F
Agent: Br
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 62.3 %

Procedure:
3-chloro-2-fluoroaniline (0.179 mL, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03) using a procedure similar to the one described in Example 3.00 to give 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (121 mg, 62.6%) as a white solid. Mass Spectrum: M+H+ 474. NMR Spectrum: (DMSOd6) 1.58 (d, 3H), 2.70 (s, 3H), 2.94 (s, 3H), 3.50-3.64 (m, 4H), 3.70-3.80 (m, 4H), 5.05-5.15 (m, 1H), 5.60 (m, 1H), 6.37 (dd, 1H), 6.44 (d, 1H), 6.65 (ddd, 1H), 6.83 (dd, 1H), 7.60 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C([O:12][C:13](=O)/[C:14](/[C:22]1[S:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=1)=[CH:15]/[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)C.CO>C1COCC1>[CH:17]1([CH2:16]/[CH:15]=[C:14](\[C:22]2[S:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)/[CH2:13][OH:12])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)/C(=C/CC1CCCC1)c1ccc(S(C)(=O)=O)s1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)c1ccc(/C(=C\CC2CCCC2)CO)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.4 %

Procedure:
Add a solution of DIBAL (5.41 mL, 1.2 M in toluene, 6.48 mmol) dropwise over one h to a solution of (Z)-4-cyclopentyl-2-(5-methanesulfonyl-thiophen-2-yl)-but-2-enoic acid ethyl ester (939 mg, max. 2.59 mmol) in THF (5 mL) at to −78 ° C. Then allow the reaction mixture to warm slowly to r.t., and stir for 18 h. Add methanol (1.5 mL) at −78° C. and allow the reaction mixture to warm to r.t. Partition the residue between ethyl acetate (15 mL) and sodium potassium tartrate (15 mL). Then extract the aqueous layer with ethyl acetate. Combine the organic layers, wash them with saturated aqueous sodium chloride solution, dry over sodium sulfate and remove solvent under vacuum to give 812 mg crude product. MS (m/e): 323.0 (M+Na).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>C1COCC1.CCOC(C)=O>[C:12]1([O:11][C:9](=[O:10])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccn1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 124.2 %

Procedure:
To a solution of 2-aminopyridine (3.0 g) in dry THF (30 mL) was added phenyl chloroformate (1.0 g, 0.8 mL) dropwise at 0° C., followed by another batch of phenyl chloroformate (1.0 g, 0.8 mL). The reaction mixture was allowed to warm to rt. After 18 h, the mixture was diluted with EtOAc (100 mL) and washed with satd. aq. NaHCO3 (20 mL). The organic layer was dried (MgSO4) and concentrated. The residue was chromatographed to give a white solid (1.7 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl[C:28]1[O:29][C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[N:32]=1.C(N(CC)CC)C.O>FC(F)(F)C(O)=O>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:28]3[O:29][C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:13][CH2:12]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCN(c3nc4ccccc4o3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
2-(4-tert-Butoxycarbonylpiperazin-1-yl)methyl-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazole prepared in Example 306 (500 mg, 1.36 mmol) was dissolved in trifluoroacetic acid (10 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and added methylene chloride (1 ml) and triethylamine (1 ml). The solution was stirred at room temperature for 5 minutes, and then concentrated under reduced pressure. The residue was dissolved in methylene chloride. To the solution, 2-chlorobenzoxazole (0.19 ml, 1.63 mmol) and triethylamine (0.23 ml, 1.63 mmol) were added followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and crystallized from methylene chloride-diisopropyl ether to afford 2-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]benzoxazole (325 mg, yield 62%) as a white powder.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)#[N:4].[CH3:14]I>CN(C)C=O>[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[N:6]=1)#[N:4]
Reactant: CI
Reactant: N#Cc1n[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nc(C#N)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (0.37 g, 60% dispersion in mineral oil) was added to a solution of 3-cyano-1H-indazole (1.20 g, Reference Example 57) in dry dimethylformamide (30 mL) under a nitrogen atmosphere at ambient temperature. The mixture was allowed to stir for 1 hour then treated with methyl iodide (0.85 mL) and stirring was continued for 1 hour. The reaction mixture was then poured into ice-water (15 mL). The precipitated solid was filtered then washed with water and then dried to give the title compound (0.80 g) as a beige solid, m.p.73° C. 1H NMR [(CD3)2SO]: δ 7.91 (m, 2H); 7.60 (t, 1H); 7.42 (t, 1H); 4.21 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.I[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>[Cu]>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1
Reactant: Oc1ccccn1
Reactant: OCc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1ccccn1-c1ccc(CO)cc1

Procedure:
2-Hydroxypyridine (10.0 mmol; 956 mg ) ,4-iodobenzyl alcohol (17.09 mmol, 4.0 g), K2CO3 (11.0 mmol, 1.52 g), and copper (0.2 mmol, 15 mg ) were mixed under argon and heated to 150° for 16 hours. The solid was partitioned between saturated NaHCO3 and EtOAc. The layers were separated and the aqueous layer was back extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to yield a yellow oil which was purified by flash chromatography (EtOAc) to give pure the title compound as a crystalline solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([C:16](OCC)=[O:17])#[C:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>CO.C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:16](=[O:17])[CH2:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)C1=Nc2cc(Cl)ccc2C(=O)C1

Procedure:
3-Chloroaniline (28.5 g, 200 mmol) and diethyl acetylenedicarboxylate (37.4 g, 220 mmol) are heated in MeOH (300 mL) for 3 h at reflux. The reaction mixture is concentrated to yield a yellow residue, which is heated in phenyl ether (400 mL), for ¾ h. The mixture is cooled to room temp. and diluted with hexane whereupon a white solid precipitates which is filtered off: 34.4 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.[Cl:38]C1C=CC=CC=1B(O)O>>[Cl:38][C:6]1[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=1[C:8]1[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[N:21]([CH3:36])[CH:22]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)[N:24]=2)[CH2:16][CH2:15]1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Reactant: OB(O)c1ccccc1Cl
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccccc2Cl)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 2-chlorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=531, obsd.=531).
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][N:12]2[C:18](=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][C:31]=1[F:32])/[CH:24]=[CH:25]/[C:26](O)=[O:27].CCN(CC)CC.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23](/[CH:24]=[CH:25]/[C:26]([N:15]2[CH2:16][CH2:17][C:18](=[O:19])[N:12]([CH2:11][CH2:10][CH2:9][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]3)[CH2:13][CH2:14]2)=[O:27])[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C/c1ccc(F)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(F)c(Cl)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1
Temperature: 0 °C

Procedure:
A suspension of 0.099 g (0.32 mmol) 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B) and 0.077 g (0.38 mmol) of (E)-3-chloro-4-fluorocinnamic acid in 3 ml of CH2Cl2 was treated with 0.09 ml (0.64 mmol) of Et3N at RT, cooled (0° C.) and treated with a 0.085 g (0.41 mmol) of N,N′-dicyclohexylcarbodiimide. The reaction was warmed up over night to RT, then partitioned between EtOAc (×3)/saturated NaHCO3. The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 and evaporated to give after purification on catridges, Si-Amine, 70 ml, 20 g (EtOAc/n-heptane 9:1) 0.075 g (64%) of the title compound as a white solid. MS: 422.1 (MH+, Cl).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[Cl:23]N1C(=O)CCC1=O>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:23])=[C:12]([F:22])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 87 %

Procedure:
6-(4-Bromo-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 28a (6.38 g, 17.51 mmol) is dissolved in N,N-dimethylformamide (275 mL). N-chlorosuccinimide (2.36 g, 17.70 mmol) is added as a solid and the reaction mixture is stirred at room temperature under N2 until the reaction is complete (5-6 days). The reaction mixture is quenched by the addition of aqueous saturated sodium bisulfite solution to give a suspension. The resulting solids are collected by filtration, washed with water and diethyl ether and dried under reduced pressure to yield 6.07 g (87%) of the pure desired product as a beige solid. MS ESI (+) m/z 398, 400 (M+ Br pattern) detected.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[CH2:17][C:16]([OH:25])([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])(=O)C.N>>[OH:25][C:16]1([C:18]2[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=2)[CH2:17][N:10]([C:8](=[O:9])[CH2:7][CH2:6][CH2:5][SH:4])[C@H:11]([C:12]([OH:14])=[O:13])[CH2:15]1
Reactant: CC(=O)SCCCC(=O)N1CC(O)(c2ccc(C)cc2)C[C@H]1C(=O)O
Agent: N
Product: Cc1ccc(C2(O)C[C@@H](C(=O)O)N(C(=O)CCCS)C2)cc1

Procedure:
The product from part (b) is treated with concentrated ammonia according to the procedure of Example 2 to yield 4-hydroxy-4-[(4-methyl)phenyl]-1-(4-mercapto-1-oxobutyl)-L-proline.
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[N+:4]([O-:7])([OH:6])=[O:5]>>[N+:4]([O-:7])([O-:6])=[O:5].[Ca+2:2].[N+:4]([O-:7])([O-:6])=[O:5]
Reactant: O=[N+]([O-])O
Agent: [Ca+2]
Agent: [OH-]
Product: O=[N+]([O-])[O-]

Procedure:
In a second embodiment of the present process, the gaseous stream is substantially completely saturated with water by addition of water thereto and the dry calcium hydroxide is added to the saturated gaseous stream which reacts with sulfur dioxide to form calcium sulfite or calcium sulfate. The gaseous stream is then exposed to a coronal discharge to form nitric acid from the nitrogen oxides. Further dry calcium hydroxide is then added to the gaseous stream which reacts with the nitric acid to form calcium nitrate. The calcium sulfite or calcium sulfate, calcium nitrate and residual calcium hydroxide, all in dry solid form, are separated from the gaseous stream and the gaseous stream discharged to the atmosphere. The dry solids are preferably separated in a baghouse filter unit and a portion of separated dry residual calcium hydroxide may be returned to the system for use in removal of sulfur dioxide and/or nitric acid from further gaseous stream.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1F)[C:5]([OH:7])=[O:6]>COCCN.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)(=[O:14])=[O:13])[C:10]=1[NH:15][CH2:16][CH2:17][O:18][CH3:19])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(Br)c(F)c(S(=O)(=O)N2CCOCC2)c1
Agent: COCCN
Agent: [Na+]
Agent: [OH-]
Product: COCCNc1c(Br)cc(C(=O)O)cc1S(=O)(=O)N1CCOCC1

Procedure:
A solution of 3-Bromo-4-fluoro-5-(morpholine-4-sulfonyl)-benzoic acid (500 mg) in 2-methoxy-ethylamine was heated at 80° C. for 3 h. The mixture was dissolved in 2 M aq. NaOH and washed with EtOAc. The aqueous layer was acidified with 2 M HCl and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated in vacuo. Yield: 575 mg.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4].I[CH2:21][CH2:22][CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:21][CH2:22][CH3:23])[CH2:11][CH2:10][CH:9]2[N:12]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1CCC2CCC1N2C(=O)OC(C)(C)C
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC1(C(=O)OC)CCC2CCC1N2C(=O)OC(C)(C)C
Temperature: -76 °C
Reaction time: 1.5 h

Procedure:
8-Azabicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a mixture of endo and exo isomers from Step 5 (1.0 g, 3.7 mmol) was dissolved in tetrahydrofuran (30 mL), and 1-iodopropane (3.2 g, 19 mmol) was added. The resulting solution was cooled to −76° C. and treated dropwise over 15 minutes with solution of potassium bis(trimethylsilyl) amide in toluene (0.5 M, 11.1 mL, 5.6 mmol). Stirring was continued at −76° C. for 1.5 hours, and the reaction mixture was then allowed to warm slowly to 0° C. over 3 hours. Saturated aqueous ammonium chloride was added, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, ethyl acetate/hexane) to provide 2-propyl-8-aza-bicyclo[3.2.1]octane-2,8-dicarboxylic acid 8-tert-butyl ester 2-methyl ester as a mixture of endo and exo isomers as a pale yellow oil (0.99 g, 85% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:25]=[C:26]([N+:28]([O-])=O)[CH:27]=1)[C:7]([O:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]1=[O:24])=[O:8])([O-])=O.Cl.[OH-].[Na+]>O1CCOCC1>[NH2:28][C:26]1[CH:25]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:27]=1)[C:7]([O:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH:15]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]1=[O:24])=[O:8]
Reactant: O=C(OCCN1C(=O)C=C(c2ccccc2)C1=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cc(N)cc(C(=O)OCCN2C(=O)C=C(c3ccccc3)C2=O)c1
Reaction time: 3 h
Yield: 91.4 %

Procedure:
In a 300 ml three-necked flask equipped with a dropping funnel and a stirring means were placed 8.22 g of N-(2-(3,5-dinitrobenzoyl)oxyethyl)-α-phenylmaleimide and 150 ml of dioxane, and 30.2 g of stannous chloride (dihydrate) was added at room temperature under stirring. Then, 30.2 g of conc. hydrochloric acid was added dropwise thereto, and thereafter, stirring was continued at room temperature for 3 hours. After completion of the reaction, a 2N aqueous solution of sodium hydroxide was added dropwise thereto until it was neutral, and the reaction solution was filtered with Celite. The filtrate was extracted twice with ethyl acetate, and the organic phase was washed three times with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure to afford a yellow solid. This solid was recrystallized twice from ethyl acetate to afford 6.42 g of N-(2-(3,5-diaminobenzoyl)oxyethyl)-α-phenylmaleimide.