Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCCCN1C=C(C2C=CC(N[C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4OC)[N:23]=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:67]([NH:69][CH3:70])=[O:68])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH:63]([CH3:66])[CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2)N=1>>[OH:65][CH2:64][CH:63]([CH3:66])[CH2:62][N:60]1[CH:61]=[C:57]([C:54]2[N:53]=[C:52]([C:67](=[O:68])[NH:69][CH3:70])[C:51]([NH:50][C:26]3[C:27]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:23]=[C:24]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:46][CH:47]=4)[N:25]=3)=[CH:56][CH:55]=2)[CH:58]=[N:59]1
Reactant: CNC(=O)c1nc(-c2cnn(CC(C)CO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)CO)c4)nc3C(=O)NC)n2)cc1)OCC

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-amino-6-[1-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-N-methylpyridine-2-carboxamide (Compound 18C) and Compound 1E with Compound 2C. 1H NMR (CD3OD, 400 MHz): δ=9.20 (br. s., 1H) 8.45 (s, 1H) 8.36 (s, 1H) 8.25 (s, 1H) 7.75 (d, J=8.8 Hz, 1H) 7.54 (d, J=7.3 Hz, 2H) 7.32 (d, J=7.6 Hz, 2H) 4.29 (dd, J=13.6, 6.32 Hz, 1H) 4.06 (quin, J=7.1 Hz, 5H) 3.47 (d, J=5.3 Hz, 2H) 3.30 (d, J=21.0 Hz, 2H, obscured) 3.00 (s, 3H) 2.21-2.32 (m, 1H) 1.25 (t, J=7.1 Hz, 6H) 0.95 (d, J=6.8 Hz, 3H). MS (ESI): m/z=677.80 [M+H]+. UPLC: tR=1.26 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[O-:34][N+:6]1[C:7]2[C:2](=[CH:1][CH:10]=[CH:9][CH:8]=2)[C:3]2[N:13]3[CH2:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][C:12]3=[N:11][C:4]=2[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3c[n+]([O-])c4ccccc4c32)C1

Procedure:
The general method described in Part E of Example 4 was used to treat tert-butyl 11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate (30.0 g, 88.6 mmol) with mCPBA (23.8 g of 77% pure material, 138 mmol) to provide tert-butyl 5-oxido-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate. The product was not dried over magnesium sulfate but was dried under high vacuum overnight.
Reaction SMILES: CC[C@:3]1([CH3:19])[N:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([OH:12])=[C:7]2[C:6](=[O:18])[NH:5][CH2:4]1.C(N[C@H](C(O)=O)C)(O[C:23](C)(C)[CH3:24])=O.[C:33](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH2:23]([N:5]1[CH2:4][C@H:3]([CH3:19])[N:8]2[CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11]([O:12][CH3:33])=[C:7]2[C:6]1=[O:18])[CH3:24]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cn2c(c1O)C(=O)NC[C@]2(C)CC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cn2c(c1OC)C(=O)N(CC)C[C@@H]2C
Temperature: 25 °C

Procedure:
To a solution of ethyl 4(S)-2-ethyl-8-hydroxy-4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (6.6 g, 25.8 mmol; prepared in a manner similar to the procedures described in Examples 32 and 45 starting with N-Boc-L-alanine) in DMF (125 mL), potassium carbonate (13.7 g, 99.1 mmol) and iodomethane (1.86 mL, 29.7 mmol) was added. The reaction mixture was stirred at rt over night. The mixture was filtered and the filtrate concentrated under vacuum. The residue was partitioned between dichloromethane and brine. The organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate to give titled material.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:7]=[C:8]([S:13][C:14]2[CH:15]=[C:16]3[C:24]([NH:25][C:26](=[O:47])[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[CH:29][C:28]=4[NH:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)=[N:23][NH:22][C:17]3=[N:18][C:19]=2[O:20]C)[CH:9]=[C:10]([F:12])[CH:11]=1.CO>ClCCl.ClCCCl>[F:5][C:6]1[CH:7]=[C:8]([S:13][C:14]2[CH:15]=[C:16]3[C:24]([NH:25][C:26](=[O:47])[C:27]4[CH:32]=[CH:31][C:30]([N:33]5[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]5)=[CH:29][C:28]=4[NH:40][CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)=[N:23][NH:22][C:17]3=[N:18][C:19]=2[OH:20])[CH:9]=[C:10]([F:12])[CH:11]=1
Reactant: COc1nc2[nH]nc(NC(=O)c3ccc(N4CCN(C)CC4)cc3NC3CCOCC3)c2cc1Sc1cc(F)cc(F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4nc(O)c(Sc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
443 μl (3 eq) of a solution of 1 M boron tribromide in dichloromethane is added to a solution of 90 mg (0.148 mmol) of N-(5-(3,5-difluorophenylthio)-6-methoxy-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (example 18) in 4 ml of 1,2-dichloroethane at 0° C. The reaction medium is stirred at 60° C. for 3 hours and then cooled in an ice bath before adding methanol. The solvents are evaporated and the residue is redissolved in a mixture of methanol and ethyl acetate. The solid formed is filtered, redissolved in 3 ml of tetrahydrofuran and is added to 1 N soda solution. The reaction medium is stirred for 18 hours at room temperature. The pH of the solution is adjusted to 8-9 and the aqueous phase is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and the crude product is purified on a silica gel column (dichloromethane/methanol as eluent) to yield 21 mg (24%) of N-(5-(3,5-difluorophenylthio)-6-hydroxy-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a yellow powder.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[N:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:28][NH:27][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:25])([F:24])[F:1])=[CH:4][C:5]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][CH:15]=3)=[N:6][C:7]=12)=[NH:13]
Reactant: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 69.1 %

Procedure:
A stirred mixture of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile [CAS-No. 851262-50-5] (2.0 g, 5.61 mmol), hydroxylamine hydrochloride (0.78 g, 11.2 mmol) and potassium carbonate (2.33 g, 16.8 mmol) in ethanol (100 ml) was heated under reflux conditions for 3 h. After the reaction mixture reached room temperature the precipitate was collected by filtration and washed with ethanol and ethyl acetate. The combined filtrates were evaporated and the crude product purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield the title compound (1.51 g, 69%) as an orange solid. MS (ISP) 389.9 [(M+H)+]; mp 252° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13](Cl)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][NH:17][CH2:18][CH2:19][CH2:20][P:21](=[O:24])([OH:23])[OH:22].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(OCC)C.O.CO>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([N:17]([CH2:18][CH2:19][CH2:20][P:21](=[O:22])([OH:24])[OH:23])[OH:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(O)(O)CCCNO
Reactant: O=C(Cl)CNC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C(NCC(=O)N(O)CCCP(=O)(O)O)OCc1ccccc1
Yield: 32.7 %

Procedure:
A solution of N-benzyloxycarbonylaminoacetyl chloride (2.85 g) in ethyl ether (5 ml) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (985 mg) and sodium bicarbonate (1.51 g) in a mixture of water (20 ml) and methanol (20 ml) with stirring under ice-cooling. During the period, the reaction mixture was adjusted to pH 7-8 with 5% aqueous sodium bicarbonate solution. The stirring was continued for an hour, whereafter the mixture was adjusted to pH 10 with 1 N aqueous sodium hydroxide solution and stirred at the same temperature for 45 minutes. The resultant mixture was adjusted to pH 7 and methanol was distilled off under reduced pressure. The resultant aqueous solution was adjusted to pH 2 with 10% hydrochloric acid and washed with ethyl acetate (30 ml), whereafter the solution was adjusted to pH 1 with 10% hydrochloric acid and then extracted twice with n-butanol (30 ml). The combined n-butanol layer was concentrated under reduced pressure to give a residue, which was crystallized from ether to give 3-[N-(N-benzyloxycarbonylaminoacetyl)N-hydroxyamino]propylphosphonic acid (720 mg) in the form of crystals MP: 101°~105° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>O.O1CCCC1>[CH:31]1[C:32]2[CH:20]([CH2:19][O:18][C:16]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])=[O:17])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: NCCCCC(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.00 g 5-aminopentanoic acid and 3.62 g of sodium carbonate in 30 ml of water was cooled to 0° C. and 4.41 g of 9-fluorenylmethyl chloroformate in 10 ml of tetrahydrofuran was added dropwise. The mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was then diluted with water and washed with ether. The aqueous solution was cooled to 0° C. and adjusted to pH 2 with 3N hydrochloric acid. The resulting white solid was collected by filtration and dried to give N-(9-fluorenylmethoxycarbonyl)-5-amino-pentanoic acid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl[CH2:15][CH2:16][C:17]#[N:18]>O>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([S:9][CH2:15][CH2:16][C:17]#[N:18])[CH:6]=[CH:7][CH:8]=1
Reactant: N#CCCCl
Reactant: FC(F)(F)c1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#CCCSc1cccc(C(F)(F)F)c1

Procedure:
A solution of 15.9 g (0.09 mol) of 3-trifluoromethylthiophenol and 3.8 g (0.095 mol) of sodium hydroxide pellets in 100 ml of water is heated at 65°-70° C and 8.5 g (0.095 mol) of β-chloropropionitrile are added dropwise whilst stirring. The mixture is heated for a quarter of an hour to the reflux temperature and is then cooled and extracted with ether, and the extract is washed with water and dried with magnesium sulphate. This gives 3-(3-trifluoromethylphenylthio)-propionitrile, which is not isolated.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:10]=[C:9]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=1.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[N+:34]([O-:36])=[O:35].CCN(C(C)C)C(C)C>CS(C)=O.CCOC(C)=O>[C:19]([C:9]1[CH:8]=[C:7]([NH:6][C:5]([NH:33][C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[C:28]([N+:34]([O-:36])=[O:35])[CH:29]=2)=[O:4])[N:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:10]=1)([CH3:21])([CH3:20])[CH3:22]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(C)c([N+](=O)[O-])c2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a mixture of 2,2,2-trichloroethyl[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]carbamate (101 mg) and (4-methyl-3-nitrophenyl)amine (38 mg) in DMSO (1 mL) was added iPr2NEt (44 under a nitrogen atmosphere and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with EtOAc (2 mL) and successively washed with 1M HCl (2 mL×2), saturated aqueous NaHCO3 (2 mL) and brine (2 mL), dried over MgSO4 and filtered. The filtrate was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with 2% MeOH in CH2Cl2 to give 1-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-3-(4-methyl-3-nitrophenyl)urea (96 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[C:4]([N+:12]([O-])=O)[CH:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[F:21][C:22]1[CH:47]=[CH:46][C:25]([C:26]([NH:28][C:29]2[S:30]C3C(N4CCOCC4)=CC=C(OC)C=3N=2)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:47]=[CH:46][C:25]([C:26]([NH:28][C:29]2[S:30][C:3]3[C:2]([N:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:7][CH:6]=[C:5]([O:8][CH:9]([CH3:11])[CH3:10])[C:4]=3[N:12]=2)=[O:27])=[CH:24][CH:23]=1
Reactant: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Reactant: C1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Product: CC(C)Oc1ccc(N2CCCCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12

Procedure:
The title compound was prepared strarting from 4-bromo-1-isopropoxy-2-nitro-benzene and piperidine as described for 4-fluoro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (Example 275) and obtained as a light brown solid in 10 % overall yield, MS: m/e=414 (M+H+).
Reaction SMILES: ClC1C=[CH:4][N:5](C(OC)=O)NC=1.[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([OH:21])=O)=[N:17][CH:18]=1.ClC1N=CC(C(Cl)=O)=NC=1.S(Cl)(Cl)=O.C(Cl)(=O)C(Cl)=O.CN>O1CCCC1>[Cl:12][C:13]1[N:14]=[CH:15][C:16]([C:19]([NH:5][CH3:4])=[O:21])=[N:17][CH:18]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: COC(=O)N1C=CC(Cl)=CN1
Agent: CN
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)c1cnc(Cl)cn1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cnc(Cl)cn1

Procedure:
Methyl 5-chloro-2-pyridazinecarboxylate (CAS#33332-25-1) is hydrolyzed to the corresponding carboxylic acid, 5-chloropyrazine-2-carboxylic acid. This acid is then converted to the corresponding acid chloride, 5-chloropyrazine-2-carbonyl chloride, by treatment with either thionyl chloride or oxalyl chloride. This acid chloride is then treated with a 2 M solution of methylamine in tetrahydrofuran to provide 5-chloro-N-methylpyrazine-2-carboxamide. The procedure of Example 48 is then repeated, substituting 5-chloro-N-methylpyrazine-2-carboxamide in place of 6-chloro-N-methyl-3-pyridinecarboxamide to give (R)—N-methyl-5-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yloxy)pyrazine-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[CH:3]=1.[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:30])[C:22]#[C:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1>>[CH3:10][O:11][C:12](=[O:37])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][N:20]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)/[C:22](=[C:23](\[C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:9])[CH:5]=3)/[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)/[C:21]2=[O:30])[CH:14]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3cc(Cl)cc(Cl)c3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1,3-dichloro-5-iodobenzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 3.92 (s, 3H), 4.95 (s, 2H), 6.47 (d, 1H), 6.65-6.78 (m, 2H), 7.13 (t, 2H), 7.33-7.43 (m, 8H), 7.52 (d, 1H), 7.93 (d, 1H), 8.01 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([NH2:21])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=23)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:41][C:42]([NH:44][CH2:45][C:46]([F:51])([F:50])[C:47](O)=[O:48])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH3:8].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:20]([NH:21][C:47](=[O:48])[C:46]([F:51])([F:50])[CH2:45][NH:44][C:42]([O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:43])=[CH:19][N:18]=[C:17]3[N:22]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:26])=[O:27])[CH:23]=[CH:24][C:16]=23)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(NCC(F)(F)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c(NC(=O)C(F)(F)CNC(=O)OCc3ccccc3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Product: N
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 0 %
Yield: 317.7 %

Procedure:
A mixture of 4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.06 mmol), 3-benzyloxycarbonylamino-2,2-difluoro-propionic acid (300 mg, 1.15 mmol), diisopropylethylamine (363 μL, 2.12 mmol) and HATU (440 mg, 1.15 mmol) in DCM (10 mL) was stirred at ambient temperature for 3.5 hours. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography on silica gel (gradient: 0 to 5% methanol in DCM then 0 to 10% 2M NH3 in methanol solution in DCM) to afford 1.20 g of 4-[1-benzenesulfonyl-5-(3-benzyloxycarbonylamino-2,2-difluoro-propionylamino)-1H-pyrrolo[2,3-b]pyridin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. LCMS (Method B, ESI): RT=3.91 min, m+H=713.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][S:45]([CH3:44])(=[O:47])=[O:46])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methanesulfonyl chloride (0.0053 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.35-2.46 (m, 2 H), 2.90 (s, 3 H), 3.06-3.20 (m, 1 H), 3.21-3.29 (m, 2 H), 3.34-3.45 (m, 2 H), 3.52-3.68 (m, 4 H), 3.72-3.83 (m, 2 H), 3.97-4.02 (m, 1 H), 4.15 (d, J=0.56 Hz, 2 H), 4.30-4.41 (m, 2 H), 7.13 (t, J=8.98 Hz, 2 H), 7.29 (s, 1 H), 7.41 (dd, J=8.84, 5.62 Hz, 2 H), 8.13 (s, 1 H), 8.56 (s, 1 H), 9.83 (br. s., 1 H), 10.32-10.41 (m, 1 H); ES+ MS: 548 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17].C(O)(C)C>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:9]([C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([CH3:8])[NH:22][C:21]=1[NH2:23])=[O:24])[CH3:17]
Reactant: CCOC(=O)C(=Cc1ccco1)C(C)=O
Reactant: CCOC(=O)CC(=N)N
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccco1
Yield: 78 %

Procedure:
Upon boiling a solution of 10.4 g of 2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 183°C (isopropanol) is obtained.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[BrH:10]>C(O)(=O)C>[Br-:10].[Br:10][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][NH+:5]=1
Reactant: OCCc1ccccn1
Reactant: Br
Solvent: CC(=O)O
Product: BrCCc1cccc[nH+]1
Product: [Br-]
Temperature: 78 °C
Yield: 73 %

Procedure:
To a solution of 2-(2-hydroxyethyl)pyridine (3 ml, 26.6 mmol) was added 30 ml of 33% HBr in acetic acid. The yellow solution was heated in the capped vial at 78° C. for 2 days. The reaction was evaporated under high vacuum to produce a brown solid. The solid was re-crystallized from hot isopropanol to produce a light tan solid (73%). 1H NMR (500 MHz, dMSO): δ 3.62-3.65 (t, 2H), 3.95-3.98 (t, 2H), 7.95 (t, 1H), 8.09-8.10 (d, 1H), 8.58 (t, 1H), 8.90 (d, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[CH:14]1[CH2:19][C:18](=[O:20])[C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[C:16]([OH:25])[CH2:15]1.N1C=CC=CC=1.O>ClCCl>[C:1]([O:12][C:10]1[CH:11]=[C:6]([CH3:5])[C:7]([CH:14]2[CH2:15][C:16](=[O:25])[C:17]([C:21](=[O:24])[CH2:22][CH3:23])=[C:18]([OH:20])[CH2:19]2)=[C:8]([CH3:13])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(O)cc2C)CC1=O
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(OC(C)=O)cc2C)CC1=O
Reaction time: 24 h
Yield: 42.4 %

Procedure:
Acetyl chloride (0.39 g; 4.9 mmole) in dichloromethane (5 ml) was added to a solution of 5-(2,6-dimethyl-4-hydroxyphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (1.29 g; 4.5 mmole) and pyridine (0.39 g; 4.9 mmole) in dichloromethane (100 ml) at room temperature. The mixture was stirred for 24 hours, then poured into water and extracted with dichloromethane. The organic extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give an oily residue. Purification by column chromatography over silica gel (eluant dichloromethane) gave 5-(4-acetyloxy-2,6-dimethylphenyl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (0.63 g; 42.0%) as a pale cream solid.
Reaction SMILES: [F:1][C:2]1([F:49])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:39]=[N:40][N:41](C3CCCCO3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[F:49][C:2]1([F:1])[CH2:7][C@H:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CC(F)(F)CC[C@@H]3c3cnn(C4CCCCO4)c3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1ccncn1)c1cc(F)c(O[C@H]2CC(F)(F)CC[C@@H]2c2cn[nH]c2)cc1F
Yield: 70.7 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 4-({(1S*,2R*)-5,5-difluoro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (170 mg, 0.24 mmol) prepared in Example 103d, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL), dichloromethane (2.0 mL) and methanol (2.0 mL), to yield the title compound (80 mg, 72%) as a colorless solid.