Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:8]([C:9]([NH2:11])=O)=[CH:7][CH:6]=[CH:5][N:4]=1.P(Cl)(Cl)([Cl:14])=O.O.[OH-].[Na+]>C(#N)C.C1(C)C=CC=CC=1>[C:9]([C:8]1[C:3]([CH2:2][Cl:14])=[N:4][CH:5]=[CH:6][CH:7]=1)#[N:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC(=O)c1cccnc1CO
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC#N
Product: N#Cc1cccnc1CCl
Temperature: 78 °C
Reaction time: 0.25 h

Procedure:
20.0 g (131.45 mmol) of 2-hydroxymethyl-3-pyridinecarboxamide are suspended in 110 ml of acetonitrile and heated to 78° C. Within 15 minutes, 60.65 g (395.52 mmol) of phosphorus oxychloride are metered in and the mixture is heated to 81° C. for 2 hours. After cooling at 22° C., the reaction mixture is stirred into 200 ml of water at 40° C. After 100 ml of toluene have been added, the mixture is neutralized with sodium hydroxide solution with cooling. After phase separation, the organic phase is washed with 100 ml of water. Removal of the organic phase and evaporation of the solvent under reduced pressure gives rise initially to an oily residue which crystallizes on standing.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52](O)=[O:53].CCN(C(C)C)C(C)C>O.CN(C)C=O>[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH2:51][C:52]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:53]
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1ccccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 2-chlorophenylacetic acid (63.8 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{1-[(2-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}thieno[3,2-c]pyridin-4-amine (85.3 mg) as a pink solid. LC/MS (ES) m/z=420.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28 (t, J=8.34 Hz, 2H) 4.02 (s, 2H) 4.32 (t, J=8.46 Hz, 2H) 5.43 (br. s., 2H) 7.23 (d, J=8.08 Hz, 1H) 7.26 (d, J=5.56 Hz, 1H) 7.31-7.37 (m, 3H) 7.39-7.44 (m, 2H) 7.45-7.51 (m, 1H) 7.83 (d, J=5.56 Hz, 1H) 8.11 (d, J=8.08 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:13](OCC)(OCC)OCC.N[C:24]([NH2:26])=O>C1(C)C(C)=CC=CC=1>[O:1]=[C:2]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:24][NH:26][CH:13]=[C:3]1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: NC(N)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1c[nH]cc(C(=O)OC)c1=O
Temperature: 25 °C
Yield: 82.3 %

Procedure:
A mixture of dimethyl 3-oxopentanedioate (12 g, 69 mmol), CH(OEt)3 (15.1 g, 100 mmol) and urea (6 g, 100 mmol) in xylene (25 mL) was heated to reflux for 3 hours. The mixture was cooled to room temperature and the precipitate was filtered, washed with xylene and DCM to afford the title compound as white solid (yield 82.3%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[CH3:28][N:29]([CH3:34])[CH2:30][C:31](O)=[O:32].O=P(Cl)(Cl)Cl>CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:23])[C:31](=[O:32])[CH2:30][N:29]([CH3:34])[CH3:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CNc1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1
Reactant: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Product: CN(C)CC(=O)N(C)c1ccc(-n2cc(CNC(=O)c3ccc(Cl)s3)nn2)cc1

Procedure:
5-Chloro-N-((1-(4-(methylamino)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (34 mg, 0.1 mmol), prepared as shown in Example 17, was dissolved in 10 mL methanol and treated with MP-carbonate for 1 hr. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in 3 mL pyridine and N,N-dimethylglycine (16 mg, 0.1 mmol) was added. The mixture was then stirred in ice bath. POCl3 (28 μL, 0.3 mmol) was added. The reaction was stirred for 20 min and quenched with methanol. The mixture was concentrated and directly subjected to prep HPLC to isolate the title compound. MS found for C19H21ClN6O2S (M+H)+ 433.1, 435.1 (Cl pattern).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23](COCC[Si](C)(C)C)[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1.C(O)(C(F)(F)F)=O.C(N)CN>C(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][NH:23][C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH2:4]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)C4CCC(CO)C4)c3)ncnc21
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC(C1CCC(CO)C1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h

Procedure:
To 3-[3-(hydroxymethyl)cyclopentyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo-[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (60.4 mg, 0.129 mmol) dissolved in CH2Cl2 (2.0 mL) was added TFA (1.0 mL) and the reaction was stirred for 1 hour at which point LCMS indicated complete cleavage to the N-hydroxymethyl intermediate (m/z=367). The triflouroacetate ester of the hydroxymethyl of the cyclopentyl ring was also observed (m/z=463). The solvent was removed and to the residue was added methanol (1.0 mL) followed by ethylenediamine (80 μL, 1.19 mmol). The resulting mixture was stirred for 16 hours at which point LCMS indicated complete reaction to the desired product. The solvent was removed and the residue was purified by chiral HPLC to provide four distinct diastereomers (20.2 mg total of four isomers, 46%). NOE experiments suggest that all isomers have cis geometry on the cyclopentyl ring. Isomers 1 and 2: 1H NMR (400 MHz, CD3OD): δ 8.65 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.40 (m, 2H), 3.22 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.10 (m, 1H), 1.94 (m, 1H), 1.82 (m, 1H), 1.6-1.4 (m, 3H), 1.03 (m, 1H). Isomers 3 and 4: 1H NMR (400 MHz, CD3OD): δ 8.66 (s, 1H), 8.62 (s, 1H), 8.37 (s, 1H), 7.50 (d, 1H), 6.95 (d, 1H), 4.51 (m, 1H), 3.46 (m, 2H), 3.21 (m, 1H), 3.11 (m, 1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.09 (m, 1H), 1.71 (m, 1H), 1.55-1.25 (m, 3H), 1.04 (m, 1H). MS (EI) m/z=337.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.[CH3:9][N:10]([CH3:14])[C:11](=O)[CH3:12].[Br:15][C:16]1[CH:17]=[C:18]([C:22]2C=C([CH:26]=[CH:27][CH:28]=2)N)[CH:19]=[N:20][CH:21]=1>O>[Br:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:12]=[C:11]([CH:26]=[CH:27][CH:28]=2)[N:10]([CH3:14])[CH3:9])[CH:19]=[N:20][CH:21]=1
Reactant: Nc1cccc(-c2cncc(Br)c2)c1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CN(C)c1cccc(-c2cncc(Br)c2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (83 mg) and methyl iodide (62 W) were added to an N,N-dimethylacetamide (1 ml) solution containing 3-(5-bromopyridin-3-yl)aniline (50 mg), followed by stirring at 80° C. for 4 hours. Water was added, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1 to 3:1), and a white solid of 3-(5-bromopyridin-3-yl)-N,N-dimethylaniline (7.1 mg) was thus obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].Cl.N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.[C:41](=O)([O:60]C1C=CC([N+]([O-])=O)=CC=1)[O:42][C@H:43]([CH2:48][N:49]1[C:53]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:52]=2[N:51]=[CH:50]1)[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:16][C@@H:4]([C@@H:3]([NH:2][C:41](=[O:60])[O:42][C@H:43]([CH2:48][N:49]1[C:53]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:52]=2[N:51]=[CH:50]1)[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Reactant: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Reaction time: 72 h
Yield: 50 %

Procedure:
73 mg (0.18 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride was slurried in 3.5 mL of anhydrous dimethylformamide. Addition of 80 mg (0.18 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl 4-nitrophenyl carbonate followed by 0.14 mL (0.72 mmol) of diisopropylethylamine resulted in a light yellow solution, which was stirred for 3 d. It was then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed with a saturated aqueous sodium bicarbonate solution., dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a methanol:chloroform solution (1:9) to afford 54 mg (50%) of (1 S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. ES-LCMS n/z 622 (M+Na) retention time=3.96 min.
Reaction SMILES: [CH3:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1COCC1.O>[CH3:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:38]([CH2:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:40])=[O:39])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(C)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(C)sc3nc(C)cc(NS(=O)(=O)Cc4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.5 %

Procedure:
To a stirred solution of 2,6-dimethyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (100 mg, 0.352 mmol) (Description 4) in THF (2 mL) cooled in an ice bath was added LiHMDS (1M solution in THF) (0.774 mL, 0.774 mmol). The reaction mixture was stirred at RT for 45 min before the addition of phenylmethanesulfonyl chloride (168 mg, 0.879 mmol). The reaction mixture was stirred at RT for a further 16 h and was then cooled in an ice bath before the addition of LiHMDS (1M solution in THF) (0.352 mL, 0.352 mmol). The reaction mixture was then stirred at RT for 1 h before the addition of phenylmethanesulfonyl chloride (67.2 mg, 0.352 mmol). The reaction mixture was stirred at RT for a further 16 h and then diluted with water (10 mL) and the aqueous layer extracted with DCM (3×20 mL). The combined organic extracts were dried over a phase separating column and concentrated. The residue was purified by MDAP (basic conditions), to afford the title compound (10 mg). LCMS (A) m/z: 439 [M+1]+, Rt 1.31 min (basic).
Reaction SMILES: [NH2:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[N:22][CH:23]=2)=[CH:13][C:10]=1[CH:11]=O.[H][H]>[Pd]>[NH2:8][C:9]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[N:22][CH:23]=2)=[CH:13][C:10]=1[CH2:11][NH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1cc(-c2ccc(O)nc2)cc(C=O)c1N
Reactant: [H][H]
Reactant: CCOC(=O)CN
Agent: [Pd]
Product: CCOC(=O)CNCc1cc(-c2ccc(O)nc2)cc(C)c1N

Procedure:
The title compound was prepared similarly to Preparation 25 using ethyl glycinate and 2-amino-5-(2-hydroxypyrid-5-yl)-3-methylbenzaldehyde followed by hydrogen over Pd/C: ##STR58##
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:7]=[CH:6][C:5]=1[CH:19]=[CH:20]OCC.C(O)(C(F)(F)F)=O.[CH:32]1([CH:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=[CH2:44])[N:38]=2)[NH2:36])[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[CH:32]1([C@H:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=[CH2:44])[N:38]=2)[N:36]2[CH2:20][CH2:19][C:5]3[C:4](=[CH:9][C:8]([O:10][C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[F:18])=[CH:7][CH:6]=3)[C:3]2=[O:24])[CH2:33][CH2:34]1
Reactant: CCOC=Cc1ccc(Oc2ccc(F)cc2F)cc1C(=O)OC
Reactant: C=Cc1cccc(C(N)C2CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1cccc([C@@H](C2CC2)N2CCc3ccc(Oc4ccc(F)cc4F)cc3C2=O)n1
Temperature: 25 °C

Procedure:
To the solution of 5-(2,4-difluoro-phenoxy)-2-(2-ethoxy-vinyl)-benzoic acid methyl ester 9 (2.09 g, 6.3 mmol) in dichloromethane (20 mL) was added 2 mL of TFA and five drops of water. The reaction was stirred at room temperature for ten minutes, at which time the solvent was removed. The crude reaction mixture was re-suspended in 100 ml of dichloromethane, extracted twice with 50 ml of saturated NaHCO3. The organic layer was dried with sodium sulfate and the solvent removed. The crude intermediate was re-suspended in 100 ml of dichloroethane and added drop wise to a 100 ml solution of dichloroethane containing cyclopropyl(6-vinylpyridin-2-yl)methanamine A20 (1.2 g, 6.9 mmol) and sodium triacetoxyborohydride (3.3 g, 15.7 mmol). The mixture was stirred at 70° C. during the drop wise addition and for additional 2 hours. The reaction was diluted with 500 mL dichloromethane and extracted with saturated brine (300 mL). The organic layer was concentrated and loaded onto a silica gel column and eluted with dichloromethane followed by separation of the enatiomers (AD-H column, 10% IPA/Hex) to give 115 mg of (R)-2-(cyclopropyl(6-vinylpyridin-2-yl)methyl)-7-(2,4-difluorophenoxy)-3,4-dihydroisoquinolin-1(2H)-one 74 as clear oil. The sterochemical configuration was assigned based on the compound 11 TLC, Rf=0.25 (CH2Cl2); Rt=20.2 min (45 min. run, AD-H chiral analalytical column, 1 ml/min, 5% IPA/Hex); 1H NMR (Methanol-D4) δ 7.69 (t, J=7.6, 1H), 7.42 (s, 1H), 7.35 (d, J=7.5, 1H), 7.29 (d, J=7.6, 1H), 7.25 (d, J=8.3, 1H), 7.09 (m, 3H), 6.97 (m, 1H), 6.78 (dd, J=10.7, 17.4, 1H), 6.18 (d, J=17.4, 1H), 5.39 (d, J=10.7, 1H), 4.99 (d, J=10.1, 1H), 3.8 (m, 2H), 2.9 (m, 2H), 1.63 (m, 1H), 0.81 (m, 1H), 0.66 (m, 1H), 0.56 (m, 1H), 0.46 (m, 1H), M+1 found 433.1; C26H22F2N2O2 requires 432.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[NH:8][CH2:7][CH2:6][CH2:5]2.[Cl:13][C:14]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23](N1C2C(=CC=CC=2)CCC1)=[O:24]>>[Cl:13][C:14]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:15]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:23]([N:8]1[C:9]2[C:4](=[CH:3][C:2]([F:1])=[C:11]([F:12])[CH:10]=2)[CH2:5][CH2:6][CH2:7]1)=[O:24]
Reactant: Fc1cc2c(cc1F)NCCC2
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2cc(F)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 1, from 6,7-difluoro-1,2,3,4-tetrahydro-quinoline (commercially available; CAS RN 953717-64-1) and 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate). Light brown gum (28%). MS (ESI): m/z=435.04 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][OH:4])[CH3:2].[H-].[Na+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21]Cl)=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1>CN(C)C=O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]3[C:18]([CH2:21][N:3]([CH2:1][CH3:2])[OH:4])=[N:19][N:20]=[C:16]3[CH2:15][N:14]=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[C:12]=2[CH:29]=1
Reactant: CCNO
Reactant: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(O)Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 16, a solution of N-ethylhydroxylamine in dimethylformamide is treated with sodium hydride suspended in mineral oil, and the mixture is treated with 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(ethylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][CH:2]1[CH:6]([OH:7])[CH:5]([CH2:8][OH:9])[CH2:4][CH:3]1[N+:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([O:18]C)=O)[CH:11]=1.[CH3:20][S:21]([O-:24])(=[O:23])=[O:22].[NH3:25]>CO>[C:16]([C:12]1[CH:11]=[N+:10]([CH:3]2[CH2:4][CH:5]([CH2:8][OH:9])[CH:6]([OH:7])[CH:2]2[OH:1])[CH:15]=[CH:14][CH:13]=1)(=[O:18])[NH2:25].[CH3:20][S:21]([O-:24])(=[O:23])=[O:22]
Reactant: COC(=O)c1ccc[n+](C2CC(CO)C(O)C2O)c1
Reactant: N
Agent: CS(=O)(=O)[O-]
Solvent: CO
Product: NC(=O)c1ccc[n+](C2CC(CO)C(O)C2O)c1
Reaction time: 2.5 h

Procedure:
Crude 1-(2,3-Dihydroxy-4-hydroxymethyl-cyclopentyl)-3-methoxycarbonyl-pyridinium-methansulfonate 118.3 g, 173.7 mmol) was dissolved in 100.0 ml methanol. After the addition of methanolic ammonia (7M, 350.0 ml, 2.45 mol) the reaction mixture was stirred for 2.5 h. After removing the solvent under reduced pressure a red-brown oil was obtained that was further dried for 3 h (40° C., 10 mbar). This crude product is pre-purified with activated charcoal and used directly for the synthesis of cNAD (WO 2007/012494).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]#[N:11].[H-].[Na+].[CH2:15]([N:19]([C:22]1[C:27]([CH3:28])=[C:26](Cl)[N:25]=[C:24]([CH3:30])[N:23]=1)[CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:15]([N:19]([CH2:20][CH3:21])[C:22]1[N:23]=[C:24]([CH3:30])[N:25]=[C:26]([CH:9]([C:2]2[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=2[CH3:12])[C:10]#[N:11])[C:27]=1[CH3:28])[CH2:16][CH2:17][CH3:18]
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc(C(C#N)c2c(C)cc(C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 107.1 %

Procedure:
A solution of mesitylacetonitrile (66 mg, 0.41 mmol) in 1 ml of DMSO was treated with NaH (60% in oil, 20 mg, 0.50 mmol) and stirred at room temperature for 20 minutes, butyl-(6-chloro-2,5-dimethylpyrimidin-4-yl)-ethylamine (100 mg, 0.414 mmol) was added and the resulting mixture was heated at 130° C. for 15 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 160 mg of brown oil. The oil was purified through silica gel column chromatography using 5% ethyl acetate in hexane as eluent to give the title compound as a brown oil. 1H NMR (CDCl3) δ 6.83 (s, 2H), 5.49 (s, 1H), 3.2–3.4 (m, 2H), 3.0–3.2 (m, 2H), 2.51 (s, 3H), 2.24 (s, 3H), 2.21 (s, 6H), 1.66 (s, 3H), 1.35–1.50 (m, 2H), 1.1–1.3 (m, 2H), 1.05 (t, 3H), 0.84 (t, 3H) ppm.
Reaction SMILES: FC(F)(F)C(O)=O.[BH4-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH:18](O)[C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[S:22][C:23]=1[CH3:24].[OH-].[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[CH2:18][C:19]1[C:20]2[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][C:21]=2[S:22][C:23]=1[CH3:24]
Reactant: COC(=O)c1ccc2sc(C)c(C(O)c3ccc(Cl)cc3Cl)c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2sc(C)c(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
Trifluoroacetic acid (30 ml) was cooled with ice, and sodium borohydride (537 mg, 14.2 mmol) was gradually added at 5-7° C. for 20 min under a nitrogen atmosphere. A solution of 3-((2,4-dichlorophenyl)hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophene in methylene chloride was added dropwise for 50 min and the mixture was stirred at room temperature for 70 min. After the completion of the reaction, the reaction mixture was poured into ice water, and trifluoroacetic acid was neutralized with 25% aqueous solution of sodium hydroxide to make the solution alkaline. The solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the objective compound (0.52 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N+:11]([O-])=O.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:11]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A mixture of 1-chloro-2,4-dinitro-benzene (100 mg, 0.5 mmol) and SnCl2.2H2O (1.12 g, 5 mmol) in ethanol (2.5 mL) was stirred at room temperature overnight. Water was added and then the mixture was basified to pH 7-8 with saturated NaHCO3 solution. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to yield 4-chloro-benzene-1,3-diamine (D-1) (79 mg, quant.).