Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.ClCl.[Cl:9][CH2:10][C:11](=[O:16])CC(Cl)=O.[C:17]1([S:23]C(O)C)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:9][CH2:10][C:11](=[O:16])[CH2:3][C:4]([O:6][CH2:2][CH2:1][S:23][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:5]
Reactant: C=C1CC(=O)O1
Reactant: O=C(Cl)CC(=O)CCl
Reactant: CC(O)Sc1ccccc1
Agent: ClCl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C(CCl)CC(=O)OCCSc1ccccc1

Procedure:
In 100 ml of methylene chloride was dissolved 35.4 g (0.421 mole) of diketene. The solution was cooled to -30° to -35° C. and 29.5 g (0.415 mole) of chlorine was bubbled into the solution for about an hour to prepare 4-chloroacetoacetyl chloride. The solution was cooled to 40° C. or below and a solution of 50 g (0.324 mole) of phenylthioethanol and 25.6 g (0.324 mole) of pyridine in 52 ml of methylene chloride was added dropwise to the solution at -20° C. or below over a period of about an hour. After completion of addition, the reaction was allowed to proceed at -5° C. for about an hour. To the reaction mixture were added 400 ml of methylene chloride and 700 ml of water to extract the reaction product. The aqueous layer was further extracted with 200 ml of methylene chloride. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give 88.5 g of phenylthioethyl 4-chloroacetoacetate as an oil.
Reaction SMILES: CON(C)C([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=O.I[C:27]1[CH:28]=[C:29]([CH3:34])[C:30]([CH3:33])=[N:31][CH:32]=1.C([Mg]Cl)(C)C.C1C[O:43][CH2:42]C1>>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:42]([C:27]3[CH:32]=[N:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=3)=[O:43])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: C1CCOC1
Reactant: Cc1cc(I)cnc1C
Agent: CC(C)[Mg]Cl
Product: Cc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cnc1C

Procedure:
Prepared from 402 mg (1.0 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 3 mL THF and 513 mg (2.2 mmol) of 5-iodo-2,3-dimethyl-pyridine in 5 mL THF with 1.15 mL 2M isopropylmagnesium chloride. Yield: 296 mg of a white powder. LC-MSD, m/z for C23H18BrN3O2 [M+H]+=448.0, 450.0; HPLC retention time: 1.9 min.
Reaction SMILES: C([O:5][K])(C)(C)C.[C:7]([CH2:9][CH2:10][N:11]=[C:12]=S)#[N:8].[F:14][C:15]([F:33])([C:20]1[CH:21]=[CH:22][C:23]2[O:28][C:27]([CH3:30])([CH3:29])[C:26](=[O:31])[CH2:25][C:24]=2[CH:32]=1)[C:16]([F:19])([F:18])[F:17].Cl>CN(C)C=O>[C:7]([CH2:9][CH2:10][NH:11][C:12]([C:25]1[C:24]2[CH:32]=[C:20]([C:15]([F:14])([F:33])[C:16]([F:19])([F:18])[F:17])[CH:21]=[CH:22][C:23]=2[O:28][C:27]([CH3:30])([CH3:29])[C:26]=1[OH:31])=[O:5])#[N:8]
Reactant: N#CCCN=C=S
Reactant: CC(C)(C)O[K]
Reactant: CC1(C)Oc2ccc(C(F)(F)C(F)(F)F)cc2CC1=O
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C(F)(F)C(F)(F)F)cc2C(C(=O)NCCC#N)=C1O
Temperature: -5 °C
Yield: 75.4 %

Procedure:
1.1 g of tertiary-butoxy potassium and 2 ml of a dimethylformamide solution of 2 g of 2-cyanoethyl isothiocyanate were subsequently added to a mixture of 2.6 g of 6-pentafluoroethyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one and 28 ml of dimethylformamide while stirring at -5° C., followed by stirring at 5° C. for 15 hours. Then, 2N hydrochloric acid was added thereto, and the mixture was extracted with ether. After washing the organic layer with water and drying, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (a developing solution, hexane:methylene chloride=1:2) to obtain 2.6 g of N-(2-cyanoethyl)-6-pentafluoroethyl-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbamide. 2.1 g of sodium cyanoborohydride was added to a mixture of 2.6 g of N-(2-cyanoethyl)-6-pentafluoroethyl-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbamide obtained above, 15 ml of acetic acid and 45 ml of tetrahydrofuran while ice-cooling and stirring, and the resulting mixture was stirred at room temperature for 13 hours. The mixture was diluted with ethyl acetate, and, after washing the organic layer with a saturated aqueous solution of sodium bicarbonate and water and drying, the solvent was distilled off to obtain 2.6 g of N-(2-cyanoethyl)-6-pentafluoroethyl-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carbamide. Then, the product was added to 90 ml of pyridine and 3.4 g of tosyl chloride, and the mixture was heated while refluxing for 1 hour. After concentration under reduced pressure, water and concentrated hydrochloric acid were added thereto, followed by extracting with methylene chloride. After washing the organic layer with water and drying, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (a developing solution, hexane:ethyl acetate=1:1) to obtain 460 mg of N-(2-cyanoethyl)-6-pentafluoroethyl-2,2-dimethyl-2H-1-benzopyran-4-carbamide having a melting point of 163°-164° C.
Reaction SMILES: [F:1][CH2:2][S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.[CH2:11](OC(OCC)OCC)C.[N-:21]=[N+:22]=[N-:23].[Na+]>>[F:1][CH2:2][S:3][C:4]1[CH:10]=[CH:9][C:7]([N:8]2[CH:11]=[N:23][N:22]=[N:21]2)=[CH:6][CH:5]=1
Reactant: Nc1ccc(SCF)cc1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Product: FCSc1ccc(-n2cnnn2)cc1

Procedure:
In accordance with the procedure described in Example 1, treatment of p-(fluoromethylthio)aniline with triethylorthoformate and sodium azide furnishes the 1-[p-(fluoromethylthio)phenyl]-1H-tetrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:37][N:38]([CH3:47])[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][N:38]([CH3:47])[CH3:37])[CH2:42][CH2:43]3)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Reactant: CN(C)CCN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine-1-carbonyl chloride (58 mg, 0.12 mmol) in CH2Cl2 (2 ml) were added Et3N (0.02 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.03 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 46 mg (63%) of the title compound as light yellow oil. ES-MS m/e: 587.3 (M+H+).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:48]1[C:43](=[CH:44][C:45]([Cl:58])=[C:46]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[CH:47]=1)[O:42][CH:41]([CH2:59][OH:60])[CH2:40]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl.[H][H]>CO.C1COCC1.[OH-].[OH-].[Pd+2]>[Cl:58][C:45]1[CH:44]=[C:43]2[O:42][CH:41]([CH2:59][OH:60])[CH2:40][C@@:10]3([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]3)[C:48]2=[CH:47][C:46]=1[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=1
Reactant: [H][H]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)OC(CO)C[C@]32O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: Clc1ccccc1Cl
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc3c(cc2Cl)OC(CO)C[C@]32O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 63.5 %

Procedure:
To a solution of 39 (17 mg, 21 umol) in a mixture of MeOH (1.5 mL) and THF (0.5 mL) were added Pd(OH)2/C (15 mg) and 1,2-dichlorobenzene (30 μL). A balloon of hydrogen gas was attached for 0.5 h with vigorous stirring. LC/MS indicated that de-protection was complete. The reaction mixture was filtered through Celite, concentrated to a residue, and purified by preparatory TLC (5% MeOH in DCM) to give 40 (6.2 mg, 64%).1H NMR (300 MHz, CD3OD) δ 7.37 (s, 1H), 7.06 (s, 4H), 6.88 (s, 1H), 4.16-4.34 (m, 1H), 3.98 (AB pattern, J=12.0 Hz, 2H), 3.88 (d, (d, J=9.6 Hz, 1H), 3.74-3.80 (m, 3H), 3.51-3.61 (m, 3H), 3.30-3.35 (m, 1H, under the solvent), 2.57 (q, J=7.5 Hz, 2H), 2.28 (d, J=13.5 Hz, 1H), 2.11 (dd, J=12.3, 15.0 Hz, 1H), 1.19 (t, J=7.5 Hz, 3H). LC/MS m/z 465 (M+H), 487 (M+Na).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH:11]=[CH:12][CH:13]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Br:7][C:8]1[CH:9]=[C:10]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(CCCCCl)c1cccc(Br)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(3-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M+H)+.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34][CH2:35][C:36]1[N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:41]([O:43]CC)=[O:42])=[CH:39][N:40]=1.[OH-].[Li+].C1COCC1>O.CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[S:34][CH2:35][C:36]1[N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=1
Reactant: CCOC(=O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(CSc2c(Cl)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
2-(((2,6-Dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (73) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 2-(((2,6-dichlorophenyl)thio)methyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (72) (1.5 g, 3.5 mmol), lithium hydroxide (1.6 g, 40 mmol), THF (50 mL), methanol (50 mL), and water (20 mL).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:22][C:23](=[O:27])[CH2:24][CH2:25]Cl)[C:12](=[O:28])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[N:29]1[CH:34]=[CH:33]C=[CH:31][CH:30]=1.[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>C1COCC1>[CH2:34]([N:29]([CH2:30][CH3:31])[CH2:2][CH2:3][C:4]([NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:22][C:23](=[O:27])[CH2:24][CH2:25][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])[C:12](=[O:28])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:33]
Reactant: CCNCC
Reactant: O=C(CCCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCCl)cccc1C2=O
Reactant: c1ccncc1
Solvent: C1CCOC1
Product: CCN(CC)CCC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CCN(CC)CC)cccc1C2=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
Add 1,8-Bis(3-chloropropionamido)anthraquinone (compound 4, 0.42 g, 1.0 mmol) with pyridine (0.5 ml) and diethylamine (0.6 ml, 6 mmole), dissolved in 20 ml dehydrated THF. The mixture is reacted in a mini-reactor. The reaction temperature is 70-80° C. in an oil bath and the reaction time is 6 hours. The reacted mixture is poured into 50 ml ice water, extracted with ethyl acetate and recrystallized from ethanol to get yellow orange compound 4a.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1I.[B:17](OC(C)C)([O:22]C(C)C)[O:18]C(C)C>CCCCCC.C1COCC1.CCOC(C)=O.Cl>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][C:8]=1[B:17]([OH:22])[OH:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ccc(Cl)c(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1ccc(Cl)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
Add, dropwise, 5.5 mL (8.8 mmol) of a 1.6N solution of butyllithium in hexane in the space of 30 min to a solution of 2.38 g (8.4 mmol) of 1-chloro-2-iodo-4-ethoxybenzene in 50 mL of anhydrous THF cooled under argon to −78° C. After 2 h at −70° C., add 1.74 g (9.2 mmol) of triisopropyl borate and stir the reaction mixture for 3 h at room temperature, then distribute in 200 mL of EtOAc/HCl aq 5N 1:1 mixture. Wash the organic phase with 50 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Purify the residue obtained by silica gel column chromatography, eluting with a DCM/methanol gradient from 0 to 10% of methanol. After concentration under reduced pressure, we obtain 990 mg of (2-chloro-5-ethoxyphenyl)boronic acid, in the form of oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=O)=[O:13])=[C:4]1[CH3:23])[CH3:2].[CH2:24]([N:26]([CH2:38][CH3:39])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH2:36][CH3:37])[CH2:34][CH3:35])[CH:28]=1)[CH3:25].C(OC(=O)C)(=O)C>C(O)C>[CH2:34]([N:33]([CH2:36][CH3:37])[C:29]1[CH:28]=[C:27]([N:26]([CH2:24][CH3:25])[CH2:38][CH3:39])[CH:32]=[CH:31][C:30]=1[C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:13]1)[CH3:35]
Reactant: CCN(CC)c1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCN(CC)c1ccc(C2(c3c(C)n(CC)c4ccccc34)OC(=O)c3ccccc32)c(N(CC)CC)c1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
A mixture of 12.28 g (0.04 mole) of 2-[(1-ethyl-2-methyl-3-indolyl)carbonyl]benzoic acid, prepared as described in part A above, 10.7 g (0.043 mole) of 90 percent active N,N,N',N'-tetraethyl-m-phenylenediamine and 6.0 ml of acetic anhydride was stirred at room temperature for seventeen hours. The reaction mixture was diluted with 26.0 ml of ethanol, stirred and filtered. The separated solid was washed with diethylether and dried to yield 11.8 g of 3-[2,4-bis(diethylamino)phenyl]-3-(1-ethyl-2-methyl-3-indolyl)phthalide (Formula III: Ro =R1 =R2 =R3 =Y1 =H; R=R6 =CH2CH3 ; R4 =N(CH2CH3)2 ; R5 =CH3), a white crystalline material which melted at 139°-140° C. The infrared spectrum showed a significant band at 1760 cm-1 (C=O; s) and the nuclear magnetic resonance spectrum was in accord with the structure. A solution of this product in benzene developed a deep blue-black color when spotted on silica gel.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH:15]=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH:18]1([O:23][C:24](=[O:33])[C@@H:25]([NH2:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:18]1([O:23][C:24](=[O:33])[C@@H:25]([NH:32][CH2:15][CH:12]2[CH2:13][CH2:14][CH:9]([CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])[CH2:10][CH2:11]2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N[C@H](C(=O)OC1CCCC1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCC(CN[C@H](C(=O)OC2CCCC2)c2ccccc2)CC1
Temperature: 25 °C
Yield: 31.3 %

Procedure:
(4-Formyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (390 mg, 1.6 mmol) and (S)-amino-phenyl-acetic acid cyclopentyl ester (394 mg, 1.8 mmol) were stirred in DCE (6 ml) at r.t. for 25 min. Acetic acid (9.6 ul, 0.16 mmol) and sodium triacetoxy-borohydride (1.0 g, 4.8 mmol) were added and the resulting mixture was stirred for 1 h30 at r.t. DCM (10 ml) and a saturated solution of NaHCO3 (10 ml) were added and phases were separated. Aqueous were extracted with EtOAc (2×10 ml), the organics were dried over magnesium sulfate, filtered and evaporated to dryness. The crude product was purified by column chromatography (8:2 heptane/EtOAc) to yield 223 mg of the pure amine (31% yield). LCMS purity 100%, m/z 445 [M++H]+.
Reaction SMILES: S(=O)(=O)(O)N.[N+:6]([O:9][S:10](=[O:13])(=[O:12])[OH:11])([O-])=[O:7].[OH:14][OH:15]>O>[O:14]=[O:15].[N:6]([O:9][S:10](=[O:12])(=[O:11])[OH:13])=[O:7]
Reactant: O=[N+]([O-])OS(=O)(=O)O
Reactant: OO
Agent: NS(=O)(=O)O
Solvent: O
Product: O=NOS(=O)(=O)O
Product: O=O

Procedure:
It should be noted that in the absence of sulfamic acid, nitrylsulphuric acid reacts with hydrogen peroxide to produce water, oxygen and nitrososulphuric acid, which material consumes yet more peroxide. This reaction sequence leads to the catalytic destruction of the peroxide added as shown in the following equations:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH3:34])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Br:35]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:33][C:13]3[N:14]([CH2:24][C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:15]=[C:16]([S:19]([CH:21]([CH3:23])[CH3:22])=[O:20])[C:17](=[O:18])[C:12]=3[C:11]=2[CH2:34][Br:35])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(-c2ccc([N+](=O)[O-])cc2)sc2c1c(=O)c(S(=O)C(C)C)cn2Cc1c(F)cccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)S(=O)c1cn(Cc2c(F)cccc2F)c2sc(-c3ccc([N+](=O)[O-])cc3)c(CBr)c2c1=O
Yield: 93.7 %

Procedure:
The compound (980 mg, 2 mmol) obtained in Example 17, N-bromosuccinimide (NBS) (0.36 g, 2.04 mmol) and α,α-azobisisobutyronitrile (AIBN) (60 mg, 0.37 mmol) were suspended in carbon tetrachloride (250 ml).The mixture was refluxed under heating for 3 hours. After cooling, the reaction mixture was partitioned between chloroform (300 ml) and an aqueous sodium bicarbonate solution. The aqueous layer was extracted with chloroform (100 ml), the extracts were combined, washed with an aqueous sodium chloride solution, dried with Na2SO4, and the solvent was distilled off. Thus obtained residue was recrystallized from dichloromethane-n-hexane to give yellow crystals (1.09 g, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7][CH2:6]2.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]([CH2:35][Cl:36])[CH2:29]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[ClH:36].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH2:26][CH2:27][N:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]([CH2:35][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:9]3=[O:15])[CH2:29]2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc2c(cc1OC)C(=O)NCC2
Reactant: COc1ccc(CCN2CCCCC(CCl)C2)cc1OC
Product: COc1ccc(CCN2CCCCC(CN3CCc4cc(OC)c(OC)cc4C3=O)C2)cc1OC
Product: Cl

Procedure:
Prepared from 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-chloromethyl-hexahydroazepine analogously to Example 2.
Reaction SMILES: [O:1]=[C:2]([CH:8]=[CH:9][C:10]1[NH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][C:4]([O:6]C)=[O:5].[OH:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24]1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(O)(=O)C>C1C=CC=CC=1.O1CCOCC1>[OH:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:9]([C:10]3[NH:11][CH:12]=[CH:13][CH:14]=3)=[CH:8][C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:24]2)=[CH:18][CH:17]=1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: COC(=O)CC(=O)C=Cc1ccc[nH]1
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: c1ccccc1
Product: O=C(O)c1cn(-c2ccc(O)cc2)c(-c2ccc[nH]2)cc1=O
Temperature: 25 °C
Yield: 46.1 %

Procedure:
In 5 ml of benzene was dissolved 1 g of methyl 3-oxo-5-(pyrrol-2-yl)-4-pentenoate and to this solution was added 0.74 g of N,N-dimethylformamidodimethylacetal. They were reacted at 70° C. for 1.5 hours. To the reaction mixture was then added 0.56 g of 4-hydroxyaniline, and they were further reacted at room temperature for 1 hour. The precipitated crystals were collected by filtration and dissolved in 10 ml of N,N-dimethylformamide. They were reacted at 140° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily substance was dissolved in 10 ml of dioxane, and to this solution was added dropwise a solution of 0.54 g of 2,3,5,6-tetrachloro-p-benzoquinone in 5 ml of dioxane at 95° C. Thereafter, the mixture was subjected to reaction at the same temperature for 30 minutes, and the reaction mixture was cooled to room temperature. The precipitated crystals were collected by filtration, dissolved in a mixture of 5 ml of methanol and 10 ml of a 10% by weight aqueous sodium hydroxide solution, and they were reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to a pH of 6.0 with acetic acid, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 0.3 g of 1-(4-hydroxyphenyl)-4-oxo-6-(pyrrol-2-yl)-1,4-dihydronicotinic acid having a melting point of 250° C. or more.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[C:9]2[CH:16]=[C:15]([C:17]3[N:21]([CH:22]4[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23]4)[CH:20]=[N:19][C:18]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:14][C:10]=2[N:11]=[CH:12][N:13]=1.O>C1COCC1.C(O)(C(F)(F)F)=O>[CH3:27][N:24]1[CH2:25][CH2:26][CH:22]([N:21]2[C:17]([C:15]3[S:14][C:10]4[N:11]=[CH:12][N:13]=[C:8]([NH2:7])[C:9]=4[CH:16]=3)=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:19]=[CH:20]2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(n2cnc(-c3ccccc3)c2-c2cc3c(N)ncnc3s2)C1
Yield: 19.8 %

Procedure:
A mixture of lithium aluminium hydride in THF (1M, 0.1 mL), THF (2 mL) and tert-butyl 3-[5-(4-aminothieno[2,3-d]pyrimidin-6-yl)-4-phenyl-1H-imidazol-1-yl]pyrrolidine-1-carboxylate (intermediate 102) (31 mg) was refluxed for 4 hours under an inert atmosphere. After addition of water and TFA (1 drop), the mixture was evaporated and the residue was purified by preparative RPHPLC (eluting with a gradient of MeCN and water containing 0.1% TFA) to afford the title compound as a colourless solid (5 mg, 28%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:14]([O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1)=[O:16]
Reactant: COc1cccc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (0-5° C.) solution of 30.0 g (0.180 mol) of 2-amino-3-methoxybenzoic acid (Aldrich Chemicals) in 500 mL of tetrahydrofuran was added 17.8 g (0.0600 mol) of triphosgene. A precipitate formed upon addition. The ice bath was removed after 15 minutes, and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into 1000 mL of water and stirred for thirty minutes. The product (mp 267-268° C.) was filtered and amounted to 32.9 g.