Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)=[CH:14][CH:15]=2)[C:10](=O)[NH:9][CH:8]=1>CC#N>[Cl:3][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH:12]=2)[C:7]([Cl:6])=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cccc(-c2ccc3c(Cl)c[nH]c(=O)c3c2)c1
Solvent: CC#N
Product: N#Cc1cccc(-c2ccc3c(Cl)cnc(Cl)c3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of POCl3 (8.36 kg, 54.5 mol) in MeCN (11.5 L) was added to a suspension of 4-chloro-7-(3-cyanophenyl)isoquinolinone (7.65 kg, 27.3 mol) in boiling MeCN (65 L) under N2 over 1 hour. The mixture was heated at reflux for 11 hours and then cooled to room temperature. The mixture was slowly quenched with 1N aqueous HCl (38.3 L) and the resultant slurry stirred for 1 hour. The solid was collected by filtration, washed with MeCN (7.6 L) and dried in vacuo at 50° C. to give 1,4-dichloro-7-(3-cyanophenyl)isoquinoline (7.20 kg, 24.1 mol, 88%) as a creamy coloured solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH2:3][C:4]([CH3:12])([CH3:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[H][H].[OH-].[Na+]>C(O)(=O)C.[Pt](=O)=O>[CH3:13][N:2]([CH3:1])[CH2:3][C:4]([CH3:11])([CH3:12])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: CN(C)CC(C)(C)c1ccncc1
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)CC(C)(C)C1CCNCC1
Yield: 93.7 %

Procedure:
A solution of 2 g (1.1×10-2 mole ) of N,N,β,β-tetramethyl-4-pyridineethanamine in 400 ml of acetic acid was hydrogenated in a Parr's apparatus at 50° C. at a hydrogen pressure of 3.106Pa in the presence of platinum dioxide. After eliminating the catalyst by filtering, the solvents were evaporated off under reduced pressure. The residue obtained was taken up in an aqueous 30% sodium hydroxide solution and extracted with methylene chloride. The organic phase was washed, dried over magnesium sulphate and filtered and the solvents were evaporated off under reduced pressure. 1.9 g (yield: 92%) of the desired compound was obtained as an oil. B Pt=60°-64° C. under 0.02 mm Hg (i.e. about 2.66 Pa)
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][C:11]3[C:14]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:15][N:16]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:10]=3[C:9]2=[O:29])=[CH:4][CH:3]=1.C(OC([N:40]1[CH2:45][CH2:44][NH:43][C:42](=[O:46])[CH2:41]1)=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].CS(C)=O>CCOC(C)=O.O.[Cu]I>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([N:16]2[C:10]3[C:9](=[O:29])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([N:43]5[CH2:44][CH2:45][NH:40][CH2:41][C:42]5=[O:46])=[CH:3][CH:4]=4)[CH2:13][CH2:12][C:11]=3[C:14]([S:25]([CH3:28])(=[O:27])=[O:26])=[N:15]2)=[CH:18][CH:19]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)N(c2ccc(I)cc2)CC3)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-n2nc(S(C)(=O)=O)c3c2C(=O)N(c2ccc(N4CCNCC4=O)cc2)CC3)cc1
Temperature: 130 °C
Yield: 35.3 %

Procedure:
To 6-(4-iodophenyl)-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1,4,5,6-tetrahydro-7H-pyrazolo(3,4-c)pyridin-7-one (0.55 g, 1.0 mmol), 4-benzyloxycarbonylpiperazin-2-one (0.35 g, 1.4 mmol), and K2CO3 (0.23 g, 1.6 mmol) was added DMSO (5 mL). The mixture was degassed with N2. CuI (39 mg, 0.21 mmol) was added and the reaction was heated to 130° C. for 18 h. The reaction was diluted with EtOAc and water, extracted with EtOAc, and dried (MgSO4). Purification of the intermediate by chromatography on silica gel using 5% MeOH/CH2Cl2 was followed by deprotection in refluxing TFA. Purification by HPLC and freeze-drying afforded 175 mg (27%) of a white solid; High Resolution Mass Spec (M+H)+ for C24H26N6O5S 496.1650.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[CH3:11][O-:12].[Na+].C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:12][CH3:11])[CH:3]=1
Reactant: C[O-]
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(Br)ccc1C#N
Yield: 79.6 %

Procedure:
In a 1 L round-bottomed flask, 53.94 g (270 mmol) of 4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodium methoxide (21.99 g, 407 mmol) was added and the mixture was heated to reflux until TLC (SiO2:CH2Cl2) showed complete consumption of starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and filtered over a plug of silica gel. The plug was eluted with CH2Cl2 and the filtrate was evaporated in vacuo to afford 45.56 g (80%) of the product as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).
Reaction SMILES: C=O.Cl.[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:37])=[C:9]([NH:11][C:12]([C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19]([NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:30][C:24]=3[N:23]=2)=[O:20])=[O:13])[CH:10]=1.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>CN(C=O)C>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:37])=[C:9]([NH:11][C:12]([C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:19]([NH:21][C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([N:31]4[CH2:32][CH2:33][N:34]([CH3:38])[CH2:35][CH2:36]4)=[CH:30][C:24]=3[N:23]=2)=[O:20])=[O:13])[CH:10]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCNCC3)ccc2[nH]1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Paraformaldehyde (0.088 g, 2.0 mmol) was weighed out into a dry 25 ml round bottom flask. N4-(5-bromo-2-methylphenyl)-N5-(5-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-imidazole-4,5-dicarboxamide hydrochloride (0.0465 g, 0.1 mmol) was added, followed by sodium triacetoxyborohydride (0.106 g, 0.5 mmol) dissolved in DMF (3.0 ml). The reaction mixture was stirred at room temperature over night (16 hours). The reaction mixture was then treated with 1 mL of 1N hydrochloric acid and concentrated under reduced pressure. The resulting crude material was purified by reverse phase HPLC (ammonium acetate/acetonitrile) which gave N4-(5-bromo-2-methylphenyl)-N5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, DMSO-d6): δ 9.83 (s, 1H), 8.28 (s, 1H), 7.88 (s, 1H), 7.45 (dd, 1H), 7.30 (m, 2H), 7.12 (m, 1H), 7.05 (m, 1H), 3.77 (d, 2H), 3.56 (d, 2H), 3.21 (d, 2H), 2.97 (m, 2H), 2.89 (s, 3H), 2.30 (s, 3H); MS (EI): 538.7 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]2[C:16]3[C:23]([C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([NH:14][C:15]2[C:16]3[C:23]([C:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:31])=[CH:22][NH:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Nc2ncnc3[nH]cc(C(=O)c4ccccc4)c23)c1
Temperature: 50 °C

Procedure:
To a mixture of tert-butyl(3-((5-benzoyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)amino)phenyl)carbamate (5.8 g, 13.5 mmol) in DCM (50 mL) was added 25 mL of TFA. The mixture was heated at 50° C. for 1 hour. Solvent was removed under reduced pressure. The residue was washed with DCM and dried on high vacuum to give an off-white solid. M.p.=280-282° C.; 400 MHz 1HNMR (DMSO-d6) δ 13.11 (s, 1H), 11.56 (s, 1H), 8.51 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.86 (d, J=7.6 Hz, 2H), 7.70 (t, J=10 Hz, 2H), 7.60 (t, J=7.2 Hz, 2H), 7.46 (t, J=8.0 Hz, 1H), 6.95 (d, J=7.2 Hz, 1H); LCMS [M+H] 330.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:41][CH3:42])[C:25]([F:43])=[CH:24][N:23]=1>>[F:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:31][C:30]=2[O:41][CH3:42])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.037 g, 39%). MP: 80-107° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.30 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.93-7.90 (m, 1H), 7.39 (s, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.49 (m, 2H), 3.93-3.88 (m, 7H), 3.86 (s, 3H), 3.27 (s, 2H), 3.17-3.12 (m, 7H), 2.98 (s, 3H), 2.91-2.85 (m, 4H), 2.74-2.65 (m, 4H). MS: 580.32 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]3[C:12](=[O:16])[O:13][C:14](=[O:15])[C:6]3=[C:5]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[CH:3]=1.[BH4-].[Na+].CC(O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][OH:16])[C:6]([C:14]([OH:15])=[O:13])=[C:5]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1OC(=O)c2c1nc1ccc(Cl)cc1c2-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=C(O)c1c(CO)nc2ccc(Cl)cc2c1-c1ccccc1
Reaction time: 4 h
Yield: 9.8 %

Procedure:
To a solution of 7-chloro-9-phenylfuro[3,4-b]quinoline-1,3-dione (prepared as described in example 9 step A, 250 mg, 0.81 mmol) in THF was added NaBH4 (30.5 mg, 0.81 mmol) at 15° C., then AcOH (92.4 μl, 1.61 mmol) was added drop wise and stirring was continued for 4 hr at room temperature. The reaction mixture was dissolved in water and the pH was adjusted to ca. 2 and extracted with ethyl acetate. The organic phases were combined and washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash column chromatography, and then further triturated with ether to give the desired product as an off-white solid (25 mg, 10%). MS (ESI): 314 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C>C1COCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2c(F)cccc2F)cc1
Solvent: Cc1cccc(C)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: [C-]#[N+]C(c1c(F)cccc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of N-[(2,6-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (2.07 g, 6.36 mmol) and THF (15 mL) is added phosphorous oxychloride (POCl3) (1.19 mL, 12.7 mmol) over a period of 5 minutes, and the resulting mixture stirred at room temperature for 10 minutes. The reaction is then cooled to 4° C. using an ice/water bath and 2,6-lutidine (4.45 mL, 38.2 mmol) is added over 30 minutes, maintaining the temperature less than 12° C. The cooling bath is removed and the mixture stirred at room temperature for 18 hours. The reaction mixture is poured into a stirred, ice water cooled solution of ice and saturated aqueous sodium bicarbonate (NaHCO3). The mixture is extracted with ethyl acetate (2×). The combined organic extracts are washed with 1N aqueous hydrochloric acid (30.0 mL), saturated aqueous sodium bicarbonate (NaHCO3) (30.0 mL), brine (30.0 mL) and dried (MgSO4). The solvents are removed in vacuo, and isopropanol (18.0 mL) is added to the residual brownish solid. The resulting slurry is stirred at room temperature for 2 hours, then water is added and the slurry stirred for an additional 30 minutes at room temperature. The slurry is filtered, the cake washed with 2:1 isopropanol-water (2×) and dried in a vacuum-oven (30° C.) for 48 hours. The title compound may be obtained as a tan solid (1.33 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([C:20]#[C:21][CH2:22][OH:23])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1>CO.C1COCC1.[Pd]>[F:1][C:2]1[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(C#CCO)cc2F)cc1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cn1cc(C(N)=O)c(Nc2ccc(CCCO)cc2F)cc1=O
Yield: 90 %

Procedure:
4-[2-Fluoro-4-(3-hydroxy-1-propynyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-[2-fluoro-4-(3-hydroxypropyl)anilino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a crystalline cream solid (90%), m.p. (EtOAc/MeOH) 214-216° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.15 (s, 1H), 8.32 (s, 1H), 7.85 (br s, 1H), 7.43 (br s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.17 (dd, J=11.8, 1.7 Hz, 1H), 7.07 (dd, J=8.2, 1.6 Hz, 1H), 5.40 (s, 1H), 4.50 (t, J=5.1 Hz, 1H), 3.41 (q, J=6.0 Hz, 2H), 3.36 (s, 3H), 2.63 (t, J=7.7 Hz, 2H), 1.76-1.69 (m, 2H). Anal. Calcd for C16H18FN3O3: C, 60.2; H, 5.7; N, 13.2. Found: C, 60.5; H, 5.8; N, 13.3.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([C:12]2[C:13]3[NH:21][N:20]=[N:19][C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)=[CH:10][CH:9]=[N:8]1.[H-].[Na+].Br[CH2:27][C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[CH2:31][NH:32]C(=O)OC(C)(C)C>CN(C=O)C>[NH2:32][CH2:31][C:30]1[CH:29]=[C:28]([CH:42]=[CH:41][CH:40]=1)[CH2:27][N:19]1[C:14]2[N:15]=[C:16]([NH2:18])[N:17]=[C:12]([C:11]3[CH:10]=[CH:9][NH:8][N:7]=3)[C:13]=2[N:21]=[N:20]1
Reactant: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2nn[nH]c12
Reactant: CC(C)(C)OC(=O)NCc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCc1cccc(Cn2nnc3c(-c4cc[nH]n4)nc(N)nc32)c1
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
A stirred solution of the 7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (330 mg, 1 mmol) in dry DMF (5 mL) was treated with NaH (40 mg, 60% in oil, 1 mmol), stirred for 15 min, treated with tert-butyl N-(3-(bromomethyl)benzyl)carbamate (300 mg, 1 mmol) and stirred for 1 h. The mixture was partitioned between EtOAc (20 mL) and H2O (20 mL), the organic phase was dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; iso-hexane:EtOAc (1:1)]. The resulting yellow syrup was dissolved in MeOH (3 mL), treated with HCl (2 mL, 4-M in dioxane), stirred for 17 h and the resulting solid filtered to give the title compound (258 mg, 80%) as a cream solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>>[CH3:16][Si:17]([CH3:19])([CH3:18])[C:20]#[C:21][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: O=S(=O)(Nc1cccc(I)c1)C(F)(F)F
Product: C[Si](C)(C)C#Cc1cccc(NS(=O)(=O)C(F)(F)F)c1
Yield: 47.9 %

Procedure:
Under the conditions of example 5A, 6.2 g of N-(3-iodophenyl)-1,1,1-trifluoromethanesulfonamide is reacted with 2.07 g of trimethylsilylacetylene, worked up, and the crude product is chromatographed on silica gel with hexane/0-25% ethyl acetate. 2.72 g of N-[3-(2-trimethylsilylethinyl)-phenyl]-1,1,1-trifluoromethanesulfonamide is obtained as yellow oil.
Reaction SMILES: S(=O)(=O)(O)O.C(O[CH:9]=[CH:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=1)=[O:12])C>>[I:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:11](=[O:12])[CH:10]=[CH:9]2
Reactant: CCOC=CC(=O)Nc1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: O=c1ccc2cc(I)ccc2[nH]1
Temperature: 0 °C
Yield: 74.1 %

Procedure:
Sulfuric acid was slowly added to 3-ethoxy-N-(4-iodo-phenyl)-acrylamide (11.3 g, 36 mmol) with stirring. After stirring for 3 hrs, the reaction mixture was slowing poured into ice (˜300 g). The precipitation was collected by filtration, washed with water and dried. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 0%-15% methanol in methylene chloride in 40 min) afforded 6-iodo-1H-quinolin-2-one (7.23 g, 75%) as a black solid. LC-MS m/e 272 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]([NH:19][CH2:20][C:21]1([CH3:26])OCCO1)=[NH:18].Cl.O.C(=O)(O)[O-].[Na+]>ClCCl>[ClH:8].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[NH:16][C:17]1[NH:19][CH:20]=[C:21]([CH3:26])[N:18]=1
Reactant: CC1(CNC(=N)Nc2c(Cl)cccc2Cl)OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: Cc1c[nH]c(Nc2c(Cl)cccc2Cl)n1
Temperature: 90 °C
Yield: 144.9 %

Procedure:
N-(2,6-Dichlorophenyl)-N′-(2-methyl-[1,3]dioxolan-2-ylmethyl)guanidine trifluoroacetic acid salt (29 mg) was mixed with 1 ml of concentrated hydrochloric acid and heated at 90° C. for 30 min. Cooling was followed by dilution with water and addition of dichloromethane. The mixture was then made alkaline with saturated sodium bicarbonate solution and extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was mixed with hydrochloric acid and freeze dried. 14 mg of the title compound were obtained.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2>CO.CCOCC>[ClH:1].[CH3:2][N:3]1[C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[C:5]2[CH:20]=[CH:21][C:22]([N:24]3[CH:29]=[CH:28][C:27]([C:30]4[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=4)=[CH:26][C:25]3=[O:40])=[N:23][C:4]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)nc31)CCNCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 94 %

Procedure:
1.25 M HCl in MeOH (4.3 mL) was added to tert-butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (47 mg, 0.087 mmol), and the resulting solution was stirred under N2 at ambient temperature for 20 h. The solution was diluted with Et2O (25 mL), and the resulting solids were collected by filtration to provide the title compound (39 mg, 94%) as a yellow solid: mp 300-305° C. dec; 1H NMR (500 MHz, DMSO-d6) δ 9.10 (s, 2H), 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.12-8.10 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.23 (dd, J=7.0, 2.0 Hz, 1H), 3.77 (s, 3H), 3.46-3.41 (m, 2H), 3.38-3.34 (m, 2H), 3.32-3.30 (m, 2H, overlapped with solvent), 3.17 (t, J=6.0 Hz, 2H); ESI MS m/z 441 [M+H]+; HPLC (Method A)>99% (AUC), tR=12.8 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([C:21](O)=O)[C:18]([OH:20])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.C(O)(=O)C.C=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]([C:18]([OH:20])=[O:19])=[CH2:21])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: C=O
Solvent: C1CCOC1
Solvent: C1COCCN1
Solvent: CC(=O)O
Product: C=C(C(=O)O)C1CCN(C(=O)OCc2ccccc2)CC1
Yield: 102.4 %

Procedure:
2-(1-Benzyloxycarbonyl-piperidin-4-yl)-malonic acid (18.06 g) was dissolved in tetrahydrofuran (140 ml) and morpholine (4.95 ml) followed by acetic acid (6.43 ml) was added, forming a white precipitate. Formaldehyde (4.56 g) was added, causing the precipitate to disappear, and the mixture heated to reflux for 4 h. The solvent was evaporated, diethyl ether (50 ml) added and the mixture extracted with water (3×60 ml). The aqueous was acidified to pH=3 with citric acid and extracted with diethyl ether (3×30 ml). The combined organic extracts were washed with water (40 ml) and brine (40 ml), dried (Na2SO4), filtered and the solvent removed under reduced pressure to give the title compound (16.65 g) as a mixture containing approximately 10% of the acid starting material.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>COCCOCCOC>[CH3:13][O:14][CH2:15][C:16]([O:12][CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)=[O:17]
Reactant: COCC(=O)OC
Reactant: OCCn1cnc2ccccc21
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOCCOC
Product: COCC(=O)OCCn1cnc2ccccc21
Yield: 65 %

Procedure:
In a nitrogen atmosphere, a mixture of crude 2-(1H-benzimidazol-1-yl)ethanol as prepared in Synthesis Example 1, 156 g of methyl methoxyacetate, 3.0 g of sodium methoxide, and 200 g of diglyme was heated under reflux for 20 hours while distilling off the methanol formed during the reaction. The solvent was distilled off in vacuo. The reaction mixture was subjected to conventional aqueous work-up and then purified by column chromatography, obtaining 2-(1H-benzimidazol-1-yl)ethyl methoxyacetate (yield 65%).
Reaction SMILES: [CH2:1]([C@@H:8]1[N:11]([Si](C(C)(C)C)(C)C)[C:10](=[O:19])[C@H:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+]>CO>[CH2:1]([C@@H:8]1[NH:11][C:10](=[O:19])[C@H:9]1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@H]1Cc1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: C[C@@H]1C(=O)N[C@H]1Cc1ccccc1
Yield: 71 %

Procedure:
To a solution of 4(S)-benzyl-1-(tert-butyldimethyl-silyl)-3(S)-methylazetidin-2-one (557 mg, 1.92 mmol) in MeOH (25 mL) at 0° was added cesium fluoride (439 mg, 2.89 mmol). After 1 h MeOH was evaporated under reduced pressure and the residue was dissolved in EtOAc. The organic phase was washed with H2O and brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (SiO2, 50% EtOAc in hexane) to give 4(S)-benzyl-3(S)-methylazetidin-2-one (239 mg, 71% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ7.35-7.17 (m, 5H), 5.78 (brs, 1H), 3.46 (ddd, J=8.0, 5.9, 2.0 Hz, 1H), 2.98 (dd, J=13.5, 5.9 Hz, 1H), 2.91 (qd, J=7.3, 2.0 Hz, 1H), 2.84 (dd, J=13.5, 8.0 Hz, 1H), 1.26 (d, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([C:21]#[N:22])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([C:21]#[N:22])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Methyl 4-{[(5-chloro-1,3-thiazol-2-yl)amino]sulfonyl}-2-cyanobenzoate (Preparation 21, 124 mg, 0.348 mmol, 1 eq) was dissolved in dioxane (2.5 ml): water (2.5 ml), lithium hydroxide (200 mg, 5 mmol, 14 eq) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 ml), washed with ethyl acetate (10 ml), acidified with 2M HCl (10 ml), extracted into ethyl acetate (10 ml), dried over sodium sulphate, filtered and evaporated to yield the title compound as a brown solid (95 mg, 0.27 mmol, 79%).