Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[S:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]12([N:21]=[C:22]=[O:23])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C([O:26]CC)C>>[C:11]12([N:21]3[C:22](=[O:23])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:26])[S:10]3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2
Reactant: S=C=NCc1ccccc1
Reactant: CCOCC
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Product: O=c1sn(C23CC4CC(CC(C4)C2)C3)c(=O)n1Cc1ccccc1

Procedure:
Reagents: Benzylisothiocyanate (6.5 mmol, 0.85 mL), 1-Adamantyl-isocyanate (6.5 mmol, 1.15 g) and SO2Cl2 (6.5 mmol, 0.52 mL) in diethyl ether (25 mL). Isolation: solvent evaporation.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[Br:19][C:20]1[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=1.C([O-])([O-])=O.[K+].[K+].[Br-]>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:22]3[S:21][C:20]([Br:19])=[N:24][N:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:20]3[S:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][N:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: O=[N+]([O-])c1nnc(Br)s1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(Br)s3)cc(C)c21
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc([N+](=O)[O-])s3)cc(C)c21
Temperature: -20 °C
Reaction time: 10 h
Yield: 26 %
Yield: 14 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.5 g, 6.0 mmol) and 2-bromo-5-nitro-[1,3,4]thiadiazole (2.52 g, 12.0 mmol) at −20° C. was added K2CO3 (1.65 g, 12.0 mmol). The reaction mixture was stirred for 10 hours at −20° C. then concentrated in vacuo. The residue was dissolved in EtOAc (20 mL), washed with water (2×10 mL), dried and concentrated. The residue was purified by silica gel flash column chromatography to give a mixture of products (5:2 nitro:bromide, 1.6 g). This was further purified by preparative HPLC to give [6-(5-bromo-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.34 g, 14%) and [1-hydroxy-4-methyl-6-(5-nitro-[1,3,4]thiadiazol-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.6 g, 26%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([C:35]1([O:38]C(=O)C)[CH2:37][CH2:36]1)=[O:34]>>[OH:38][C:35]1([C:33]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=5[O:27][CH2:28][CH2:29][O:30][CH3:31])[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:3][CH2:2]2)=[O:34])[CH2:37][CH2:36]1
Reactant: CC(=O)OC1(C(=O)Cl)CC1
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCNCC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)NC3CCN(C(=O)C4(O)CC4)CC3)c[nH]c12

Procedure:
Starting from 4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A184) and acetic acid 1-chlorocarbonyl-cyclopropyl ester the title compound was obtained as colorless solid.
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH:4]([CH3:7])[CH2:5][CH3:6].COC(=O)[C@H]([C@H](CC)C)N.OCCN.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[S:33])=[C:27]([CH2:34][CH3:35])[CH:26]=1)#[N:24]>>[C:23]([C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]2[NH:8][C@@H:3]([CH:4]([CH2:5][CH3:6])[CH3:7])[CH2:2][S:33]2)=[C:27]([CH2:34][CH3:35])[CH:26]=1)#[N:24]
Reactant: CCC(C)[C@H](N)CO
Reactant: CCc1cc(C#N)ccc1N=C=S
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCc1cc(C#N)ccc1N=C1N[C@@H](C(C)CC)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Cyano-2-ethylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-cyano-2-ethylphenylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH3:21])=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1>>[ClH:28].[CH2:1]([NH:8][C:9]1[N:13]([CH2:14][CH3:15])[C:12]2[CH:16]=[CH:17][C:18]([N:20]([CH3:21])[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([CH2:36][S:37]([NH2:40])(=[O:38])=[O:39])=[CH:32][CH:31]=4)[N:23]=3)=[CH:19][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Cl)n3)ccc21
Product: CCn1c(NCc2ccccc2)nc2cc(N(C)c3ccnc(Nc4ccc(CS(N)(=O)=O)cc4)n3)ccc21
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N2-Benzyl-N5-(2-chloro-pyrimidin-4-yl)-1-ethyl-N5-methyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) as a white solid (97 mg, 67%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.30 (s, 1H), 7.79 (d, J=6.0 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 7.15-7.42 (M, 9H), 6.9+5 (d, J=8.1 Hz, 1H), 6.77 (s, 2H), 5.69 (d, J=6.0 Hz, 1H), 4.65 (d, J=5.7 Hz, 2H), 4.16-4.18 (m, 4H), 3.44 (s, 3H), 1.27 (t, J=7.2 Hz, 3H). MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:20][CH2:21][CH2:22][OH:23])=[O:9])([CH3:6])[CH3:5].[CH2:25]1[C:33]2[C:28](=[CH:29][C:30](O)=[CH:31][CH:32]=2)[CH2:27][CH2:26]1.CCOC(/N=N/C(OCC)=O)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C>[CH2:25]1[C:33]2[C:28](=[CH:29][C:30]([O:23][CH2:22][CH2:21][O:20][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:18]=[CH:19][C:10]=3[C:8]([NH:7][C:4]([CH3:5])([CH3:6])[C:3]([OH:2])=[O:24])=[O:9])=[CH:31][CH:32]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OCCO
Reactant: Oc1ccc2c(c1)CCC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1ccc2ccccc2c1OCCOc1ccc2c(c1)CCC2)C(=O)O

Procedure:
Under inert atmosphere to 166 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester, 74 mg indan-5-ol and 208 mg polystyrene-bound triphenyl phosphine (3 mmol/g) in 5 ml THF at 0° C. 98 μl diethylazodicarboxylate were added. After 16 h at room temperature the reaction was filtrated, the filtrate concentrated in vacuo and after RP-HPLC the obtained 2-({1-[2-(Indan-5-yloxy)-ethoxy]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester was dissolved in 3 ml of dioxane and reacted with 3 ml 1N NaOH for 5 h at 50° C. The reaction was then diluted with ethyl acetate and treated with citric acid (5%). The organic layer was separated, dried and concentrated in vacuo. After purification by RP-HPLC 22 mg 2-{[1-(2-hydroxy-ethoxy)-naphthalene-2-carbonyl]-amino}-2-methyl-propionic acid were obtained.
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:21]2=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)CNC
Reactant: CC(C)(C)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CC(=O)N(c2ccc(C(C)(C)C)cc2)C1=S
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 4-t-butylphenylisothiocyanate (9.6 g), triethyl amine (10.1 g) and chloroform (250 mL) was heated at reflux for 3 hours. The mixture was cooled to ambient temperature, washed with 2N HCl (2×200 mL), then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.9 g), m.p. 156°-158° C. Anal. Calcd. for C14H18N2O S: C, 64.09; H, 6.91; N,10.68. Found: C, 63.83; H, 7.15; N, 10.53. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:20][C:15]3[CH2:16][NH:17][CH2:18][CH2:19][C:14]=3[C:13]=2[C:21]([NH2:23])=[O:22])=[O:10])=[C:4]([F:24])[CH:3]=1.[CH:25]1[CH:26]=[CH:27][C:28]2[N:33](O)[N:32]=[N:31][C:29]=2[CH:30]=1.CCN=C=NCCCN(C)C.Cl.CN([CH:50]=[O:51])C>>[NH:31]1[C:29]2[CH:30]=[CH:25][C:26]([C:50]([N:17]3[CH2:18][CH2:19][C:14]4[C:13]([C:21]([NH2:23])=[O:22])=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:24])[S:20][C:15]=4[CH2:16]3)=[O:51])=[CH:27][C:28]=2[N:33]=[N:32]1
Reactant: NC(=O)c1c(NC(=O)Cc2ccc(Cl)cc2F)sc2c1CCNC2
Reactant: CN(C)C=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: NC(=O)c1c(NC(=O)Cc2ccc(Cl)cc2F)sc2c1CCN(C(=O)c1ccc3[nH]nnc3c1)C2
Temperature: 80 °C
Yield: 12 %

Procedure:
Starting material 20 (118 mg, 0.3 mmol) was suspended in 2 ml dry DMF and 1H-1,2,3-benzothiazole-5-carboxyllic acid (63 mg, 0.4 mmol, 1.2 equiv.), dry HOBt (52 mg, 0.4 mmol) and EDCl (74 mg, 0.4 mmol) were added. The brown suspension was stirred at 80° C. over night. Then another 0.5 equiv. 1H-1,2,3-benzothiazole-5-carboxyllic acid were added and the reaction was stirred another 6 h at 80° C. the solvent was reduced under vacuo and the remaining crude product further purified by prep. HPLC (Method 3). The pure fractions were combined and the solvent was reduced. The remaining product was lyophilized yielding the desired products 21 as a light-brown solid (20 mg, 0.04 mmol, 12%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][CH:30]([CH3:39])[CH:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)[OH:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:29][CH:30]([CH3:39])[CH:31]([CH:33]1[CH2:38][CH2:37][N:36]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:35][CH2:34]1)[OH:32]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)C(O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(O)C(C)C)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.5 %

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (200 mg, 0.53 mmol), 2-methyl-1-piperidin-4-yl-propan-1-ol (125 mg, 0.79 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (10 mL) was stirred at RT under nitrogen atmosphere for 1.5 h. Sodium triacetoxyborohydride (167 mg, 0.79 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with DCM/MeOH, the desired product was subsequently eluted using a mixture of 2M NH3 in MeOH and DCM. The residue was purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 5:95) followed by a further purification (Si—PCC, acetone:cyclohexane: gradient 10:90 to 40:60). The solvents were reduced in vacuo to afford 346 as a white solid (114 mg, 41%). LCMS (Method G): RT 6.81 min, [M+H]+ 519. 1H NMR (400 MHz, CH3OH-d4): δ 8.06-8.05 (1 H, m), 7.56-7.55 (1 H, m), 7.25-7.24 (2 H, m), 4.29 (4 H, br s), 3.84 (3 H, s), 3.81 (4 H, t, J=4.74 Hz), 3.74 (2 H, s), 2.98-2.95 (3 H, m), 2.86 (3 H, s), 2.11 (2 H, m), 1.84 (1 H, m), 1.72-1.71 (1 H, m), 1.57-1.20 (4 H, m), 0.87 (6 H, dd, J=15.35, 6.73 Hz)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19](I)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1.C([Sn](Cl)(CCCC)CCCC)CCC.Br[C:57]1[S:61][C:60]([C:62]([NH2:64])=[O:63])=[CH:59][CH:58]=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:57]5[S:61][C:60]([C:62]([NH2:64])=[O:63])=[CH:59][CH:58]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)s1
Reactant: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(I)n3c2)cc1
Agent: CCCC[Sn](Cl)(CCCC)CCCC
Solvent: Cc1ccccc1C
Product: NC(=O)c1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)s1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A mixture of 200 mg 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-(1,1,1-tributylstannyl)imidazo[1,2-a]-pyridine prepared from 6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 39) and tributyltin chloride by the same method as in Production Example 48, 51 mg 5-bromo-2-thiophene carboxamide, 14 mg tetrakis (triphenylphosphine)palladium and 3 mL xylene was stirred at 120° C. for 2 hours under nitrogen atmosphere. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/methanol) to give 37 mg of the title compound as a colorless amorphous.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9](Cl)[N:10]([CH3:12])[CH3:11])#[N:2].[F-:17].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>C(#N)C>[C:1]([C:3]1[C:4]([CH:14]([CH3:16])[CH3:15])=[N:5][S:6][C:7]=1[N:8]=[C:9]([F:17])[N:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CC(C)c1nsc(N=C(Cl)N(C)C)c1C#N
Reactant: [F-]
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: CC(C)c1nsc(N=C(F)N(C)C)c1C#N
Yield: 20.9 %

Procedure:
A mixture of 12.8 g of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, 2.9 g of potassium fluoride and a catalytic amount of 2,3,11,12 -dibenzo-1,4,7,10,13,16-hexaoxacyclooctadeca-2,11-diene, in 60 ml of acetonitrile was stirred at ambient temperature for 12 hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was recrystallized from diethyl ether to give 2.5 grams of N'-(4-cyano-3-isopropyl-5-isothiazolyl)-N,N-dimethylfluoroformamidine, mp 100°-102°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8])([CH3:3])[CH3:2].[C:12](Cl)(Cl)=[S:13].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]=[C:12]=[S:13])[CH:9]=[CH:10][CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(N)c1
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Oc1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHCl3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:24][CH2:25][C:26](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:23])[N:9]3[CH2:22][CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:26]([CH2:25][Cl:24])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCl)OC(=O)CCl
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Reaction time: 2 h
Yield: 75.4 %

Procedure:
A suspension of 7.07 g (21.3 mmol) of (S)-8-chloro-9-oxo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime in 50 ml of N,N-dimethylformamide was treated with 4.0 g (23.4 mmol) of chloroacetic anhydride. The yellow solution obtained was stirred at 105° for 2 hrs. and then completely freed from the solvents. The oily product was chromatographed over silica gel with methylene chloride/methanol 9:1 as the eluent and the oily product obtained was recrystallized from ethyl acetate/ether. The mother liquor was concentrated, the residue was again chromatographed over silica gel with acetonitrile as the eluent and the additional portion of product obtained was recrystallized from ethyl acetate/ether. There were obtained a total of 6.27 g (75%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as white crystals; m.p. 184°-186° and [α]D20 =+36.1° (MeOH, c=1%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([O:8][CH2:9][CH3:10])[C:6]=1N.[Cl:11][CH2:12][C:13](Cl)=[O:14].O.[CH3:17][N:18](C)C=O>C(N(CC)CC)C>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[S:3][CH:4]=[C:5]([O:8][CH2:9][CH3:10])[C:6]=1[C:17]#[N:18])=[O:14]
Reactant: CN(C)C=O
Reactant: O=C(Cl)CCl
Reactant: CCOc1csc(N)c1N
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1csc(NC(=O)CCl)c1C#N
Reaction time: 4 h

Procedure:
168 parts of 2-amino-3-amino-4-ethoxythiophene are dissolved in 500 parts by volume of dimethylformamide, 101 parts of triethylamine are added, and 130 parts of monochloroacetyl chloride are introduced dropwise at 50° C. Stirring is continued for 4 hours at 50° C., after which the reaction mixture is poured onto 2000 parts of water. The product is filtered off under suction, washed with water and dried, and 240 parts of 2-(2-chloroacetylamino)-3-cyano-4-ethoxythiophene are obtained. A sample recrystallized from acetic acid melts at 243°-244° C. and has a chlorine content of 14.1% (calculated: 14.5%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl>[Cl:12][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=1
Reactant: OCc1ccc(F)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Fc1ccc(CCl)nc1
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-methanol (945 mg, 7.43 mmol) described in Manufacturing Example 41-1-1 in methylene chloride (70 mL) was added dropwise thionyl chloride (813 μL, 11.1 mmol) at room temperature, which was stirred for 30 minutes. This reaction solution was partitioned by addition of water, sodium hydrogencarbonate and methylene chloride. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:diethyl ether=1:1) to obtain the title compound (761.1 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>[Pd].CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
Place 4-(5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.14 g, 3.70 mmol) in 1:1 EtOAc:MeOH (20 mL). Add 10% Pd on carbon using EtOAc (5 mL). Purge the reaction and then add hydrogen. Repeat the purge/fill cycle twice and place the reaction under a balloon of hydrogen and stir at room temperature for 20 hours. Filter the reaction through a pad of Celite® and wash the filter cake with EtOAc. Collect the filtrate and concentrate under reduced pressure to yield 1.01 g (98%) of the title compound. MS(ES): m/z=279 [M+H].
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]3[O:30][C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:24]4[O:23][CH2:22]3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[CH3:32][C:33]1([OH:39])CCNCC1>>[O:23]1[C:24]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][C:33]([CH3:32])([OH:39])[CH2:9][CH2:10]3)=[CH:16][CH:17]=2)[CH2:22]1
Reactant: CC1(O)CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: Cl
Product: CC1(O)CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
Compound 276 is synthesized from Intermediate C and Intermediate R according to General Method K. (LC/MS method 16: ES+ m/z 341.2 [M+H]+, Rt=2.50 min)
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[2H]Cl.[C:12]([O:18][CH3:19])(=[O:17])[CH2:13][C:14]([CH3:16])=O.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9]/[C:14](/[CH3:16])=[CH:13]\[C:12]([O:18][CH3:19])=[O:17])[CH3:2]
Reactant: COC(=O)CC(C)=O
Reactant: CCN1CCCC1CN
Agent: O=S(=O)([O-])[O-]
Agent: [2H]Cl
Agent: [Mg+2]
Solvent: ClCCl
Product: CCN1CCCC1CN/C(C)=C\C(=O)OC
Yield: 81.1 %

Procedure:
38.4 G (0.3 MOLE) OF N-ethyl-2-aminomethylpyrrolidine and a drop of hydrochloric acid d=1.18 were added into a 250 ml flask provided with a stirrer, a thermometer, a condenser and a dropping funnel; 34.8 g (0.3 mole) of methyl acetoacetate were added drop by drop. The temperature reached 54° C. by the end of the introduction. The mixture was next allowed to return to ambient temperature while stirring, and 150 ml of methylene chloride and 5 g of magnesium sulphate were then added. The mixture was stirred for one hour, filtered, the solvent was vaporated in vacuo, and the residue was distilled. 55 g of methyl N-(1-ethyl-2-pyrrolidylmethyl)-3-aminocrotonate were obtained. (Yield: 81.1%; boiling point--3 mm/Hg: 132°-134° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1(=O)[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1.[CH2:16](O)C>[C].[Pd]>[OH:14][C:11]1[CH:12]=[CH:13][C:1]([N:2]2[CH2:7][CH2:6][CH:5]([CH3:16])[CH2:4][CH2:3]2)=[CH:9][CH:10]=1
Reactant: CN1CCCCC1
Reactant: CCO
Reactant: O=C1CCC(=O)CC1
Agent: [Pd]
Product: CC1CCN(c2ccc(O)cc2)CC1
Yield: 65.5 %

Procedure:
1.00 g of 1-methylpiperadine, 1.68 g of 1,4-cyclohexanedione and 40 mg of 10% palladium-carbon were heated with stirring in 40 ml of ethanol at 50° C. to 60° C. and reacted for 8 hours under air bubbling. During the reaction, ethanol was added as needed. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resultant was purified by silica gel column chromatography (ethyl acetate:methanol=3:1) and 1.26 g of 1-(4-hydroxyphenyl)-4-methylpiperadine was obtained (yield 65.5%).