Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C@H:19]([NH:21][C:22]([C:24]3([CH3:35])[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[C@@H:31]([NH2:33])[CH3:32])[NH:25]3)=[O:23])[CH3:20])=[N:16]2)=[CH:11][CH:10]=1.[OH:36][C@@H:37]([CH:41]([CH3:43])[CH3:42])[C:38](O)=[O:39].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([C@H:19]([NH:21][C:22]([C:24]3([CH3:35])[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:34])[C@@H:31]([NH:33][C:38](=[O:39])[C@@H:37]([OH:36])[CH:41]([CH3:43])[CH3:42])[CH3:32])[NH:25]3)=[O:23])[CH3:20])=[N:16]2)=[CH:11][CH:10]=1
Reactant: CC(C)[C@H](O)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCCC(C)(C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCCC(C)(C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.8 %

Procedure:
To a solution of ((S)-2-{3-[(R)-1-(7-bromo-quinolin-2-yl)-thylcarbamoyl]-3-methyl-tetrahydro-pyridazin-1-yl}-1-methyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.92 g, 3.5 mmol) in dichloromethane (15 mL) at 0° C. was added trifluoroacetic acid (3 mL). The reaction mixture was allowed to warm to room temperature and then stirred for 4 h. The reaction mixture was concentrated and the residue was co-evaporated with toluene (3×) to give 1-((S)-2-amino-propionyl)-3-methyl-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide trifluoroacetate salt (3.5 mmol) as a brown oil. LCMS (m/z) 448.0, 450.0 [M+H], Tr=1.22 min. 1-((S)-2-Amino-propionyl)-3-methyl-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide trifluoroacetate salt (3.5 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to 0° C. (S)-2-Hydroxy-3-methyl-butyric acid (458 mg, 3.8 mmol), N,N-diisopropylethylamine (5 mL, 28.0 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (1.86 g, 4.2 mmol) were added. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic solution was washed with citric acid (10%), saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with a gradient of ethyl acetate/methanol 1:0 to 20:1 to afford the title compound (745 mg, 39% over 2 steps) as a white foam and as a 1:4 mixture of diastereoisomers. LCMS (m/z) 548.0, 550.0 [M+H], Tr=2.21 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([OH:25])=O.[N:43]1[CH:48]=[CH:47][C:46]([NH:49][CH2:50][CH2:51][NH2:52])=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([NH:52][CH2:51][CH2:50][NH:49][C:46]1[CH:47]=[CH:48][N:43]=[CH:44][CH:45]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: NCCNc1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)NCCNc1ccncc1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 2-(pyridin-4-yl-amino)-ethylamine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a cooled solution of 4-tert-butyl-2-(5-methoxybenzofuran-2-yl)thiazole (1.0 g) in dichloromethane (10 ml), 1M solution of boron tribromide in dichloromethane (7 ml) was added dropwise at 5° C. After being stirred for 3 hours, the resulting solution was poured into a mixture of ice and aqueous sodium hydrogen carbonate. The resulting precipitates were collected by filtration and dissolved in a mixture of tetrahydrofuran and water. The solution was concentrated to give crystals of 4-tert-butyl-2-(5-hydroxybenzofuran-2-yl)thiazole (0.91 g).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[CH2:7][NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH:16]=[C:7]1[NH:6][C:5](=[O:10])[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]1=[O:9])[CH3:15]
Reactant: COC(OC)N(C)C
Reactant: CC(C)N1C(=O)CNC1=O
Product: CC(C)N1C(=O)NC(=CN(C)C)C1=O
Temperature: 100 °C

Procedure:
A mixture of 5 g of 3-isopropylimidazolidine-2,4-dione and 5 ml dimethylformamide dimethylacetal were heated at 100° C. for 3 s. The reaction mixture was cooled to rt and purified by flash chromatography to give 2 g of an orange solid. 1H NMR (400 MHz, deuteriochloroform): δ=1.42 (6H, d, J=7 Hz), 3.11 (6H, s), 4.40 (1H, septet, J=7 Hz), 6.64 (1H, s), 9.55 (1H, br s).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[CH2:6]([Li])[CH2:7][CH2:8]C.[I:11]I>O1CCCC1>[I:11][C:8]1[N:3]([CH:4]=[CH2:5])[N:2]=[N:1][C:7]=1[CH3:6]
Reactant: c1c[nH]nn1
Reactant: II
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: C=Cn1nnc(C)c1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a cold (−78° C.) solution of the triazole from preparation 59 (3.0 g, 12.4 mmol) in tetrahydrofuran (70 mL), under an atmosphere of nitrogen, was added n-butyllithium (2.5M in hexane, 5.5 ml, 14 mmol, 1.1 eq.) at such a rate as to maintain the temperature below −70° C. The resulting yellow solution was stirred at −78° C. for 2 hr before adding a solution of iodine (3.47 g, 13.7 mmol, 1.1 eq.) in tetrahydrofuran (10 mL). The resulting mixture was allowed to slowly warm to room temperature over 2 hr before concentrating the mixture by evaporation under reduced pressure. The residue was partition between tert-butyl methyl ether (150 mL) and a mixture of aqueous sodium hydrogen carbonate (1M, 50 mL) and aqueous sodium sulphite (1M, 100 ml). The organic phase was washed with saturated brine (20 mL) and dried over sodium sulphate. The resulting mixture was filtered and the filtrate concentrated under reduced pressure to give an orange solid. The crude solid was purified by chromatography on silica gel (100 g) eluting with a gradient of ethyl acetate in heptane (10:90 to 50:50) to give the title compound as a white solid (1.6 g, 55%).
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[CH3:35][N:33]([CH3:34])[C:32]([CH:20]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:11][CH:10]=2)=[CH:18][CH:17]=1)=[O:36]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NS(=O)(=O)c3ccc(C)cc3)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
The sulfonamide compound 24 (0.9 g, 1.72 mmol) was dissolved in THF (10 mL) and diluted with water (10 mL). Lithium hydroxide (0.16, 6.86 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×25 mL). The organic layer was washed with water (1×25 mL) and brine (1×25 mL), dried and concentrated to yield the desired acid compound 25 (0.9 g, quantitative). 1H NMR (400 MHz, DMSO-d6): 12.2 (br, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.6 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.28 (m, 1H), 2.75-2.81 (m, 3H), 2.69 (s, 3H), 2.60 (dd, J=13.2 and 7.6 Hz, 1H), 2.52 (t, J=8.0 Hz, 2H), 2.35 (s, 3H). LCMS (m/e): Obsd. 526, Calcd. 525.62
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:25]=[CH:24][S:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:25]=[CH:24][S:23][CH:22]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Reactant: BrCc1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccsc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 582 mg (2.37 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 10 mL DMF is added 0.70 g (3.95 mmol) 3-bromomethyl-thiophene and 1.64 g (11.9 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, filtered and is directly transferred to a reverse HPLC for purification (Zorbax stable bond C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: O1CCCC1.B.[O:7]=[C:8]([CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]>C1(C)C=CC=CC=1>[OH:7][C@H:8]([CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCCC(C)=O
Agent: B
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCCC[C@@H](C)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
(S)-methyloxazaborolidine (8.77 g, 31.63 mmol) dissolved in 30 mL of toluene. The solution was cooled to 0° C. and the borane tetrahydrofuran complex (31.6 mL of 1.0M solution in THF, 31.6 mmol) was added. After 30 min the ketone 24 (5.0 g, 31.63 mmol) was added. The reaction solution was stirred for 4 h and was then quenched by slow addition of saturated aqueous ammonium chloride. The resultant mixture was extracted with EtOAc (2×). The combined organic portions were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Flash column chromatography (silica gel, 3:1 hex/EtOAc) afforded 2.58 g (51%) of the alcohol 25 (see scheme 4).
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][N:6]1[C:10](Cl)=[N:9][N:8]=[N:7]1)C.NC(N)=[S:15].O.Cl>C(O)C>[SH:15][C:10]1[N:6]([CH2:5][C:4]([OH:3])=[O:12])[N:7]=[N:8][N:9]=1
Reactant: CCOC(=O)Cn1nnnc1Cl
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)Cn1nnnc1S

Procedure:
In a 500 ml round flash equipped with agitator, relux condenser, thermometer and a dropping funnel a mixture of 100 g (0.52 mol) 5-Chloro-1H-tetrazole-1-acetic acid ethyl ester, 44 g (0,57 Mol) thiourea, 210 g water and 25 g of 38 wt.% aqueous hydrochloric acid was heated to reflux for 6 hours, while the ethanol formed during the reaction was distilled off. For working up purpose, the residue was extracted with methyl isobutyl ketone. After evaporation of the ketone 57.9 g=69% of the theory of a white crystalline solid (melting point 173° C.) of 5-Mercapto-1H-tetrazole-1-acetic acid was obtained (purity 99%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C-:17]#[N:18].[K+].OS([O-])=O.[Na+]>C1COCC1.O>[C:17]([C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1)#[N:18]
Reactant: [C-]#N
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(O)CCN(C(=O)OCc2ccccc2)C1
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a stirred solution of phenylmethyl 3-oxo-1-pyrrolidinecarboxylate (1.0 g, 4.56 mmole) and KCN (0.81 g, 12.54 mmole) in THF (5 mL) and H2O (15 mL) at 0° C. was added NaHSO3 (1.14 g, 10.9 mmole) in H2O (5.0 mL). After 3 h, the reaction contents were concentrated in vacuo, extracted with CHCl3 (2×100 mL), and the organics dried over Na2SO4. Purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (0.92 g, 82%) as a light yellow oil: LC-MS (ES) m/e 247 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH2:18])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N:20]1[N:21]([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:23][CH:24]=1.C(Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:12][C:13]2([CH3:19])[CH2:17][CH2:16][CH2:15][CH:14]2[NH:18][C:31]([C:26]2[C:25]([N:21]3[N:22]=[CH:23][CH:24]=[N:20]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:32])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1N
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CC1(Nc2ncc(C(F)(F)F)cc2F)CCCC1NC(=O)c1ncccc1-n1nccn1

Procedure:
A solution of 1-N-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]-1-methylcyclopentane-1,2-diamine (Intermediate 28; 57 mg, 0.21 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 51 mg, 0.27 mmol), EDC (51 mg, 0.27 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (36 mg, 0.27 mmol) and triethylamine (0.086 ml, 0.62 mmol) in DCM (3 ml) was stirred at room temperature for 18 hours. The reaction was then diluted with DCM (20 ml) and a saturated solution of sodium bicarbonate (10 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([OH:19])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:20][Si](C=[N+]=[N-])(C)C>C(Cl)Cl.CO>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C1C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid (SNPE, 10 g, 38 mmol) in CH2Cl2 (100 mL) and MeOH (100 mL) at 0° C. was added trimethylsilyldiazomethane dropwise until the yellow color persisted. After stirring at rt for 15 min, the reaction mixture was concentrated in vacuo. The residue was azeotroped with toluene to afford N-BOC-1,3-dihydro-2H-isoindol-1-carboxylic acid, methyl ester which was used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Cl:7][C:8]1[S:32][C:11]2[NH:12][C:13]([C:15]([NH:17][CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:28][C:29]#[N:30])[C:19]3=[O:31])=[O:16])=[CH:14][C:10]=2[CH:9]=1>CO.C1COCC1.CCOC(C)=O>[NH2:30]/[C:29](=[N:2]\[OH:3])/[CH2:28][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:27][CH:18]([NH:17][C:15]([C:13]2[NH:12][C:11]3[S:32][C:8]([Cl:7])=[CH:9][C:10]=3[CH:14]=2)=[O:16])[C:19]1=[O:31]
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21)=N\O
Reaction time: 18 h
Yield: 101.2 %

Procedure:
Hydroxylamine hydrochloride (181 mg, 2.60 mmol) in MeOH (5 mL) was added to a solution of NaOMe in MeOH (10.20 mL, 0.25M) under an inert atmosphere followed by 2-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 27; 500 mg, 1.30 mmol) in THF (7 mL) then stirred for 18 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (25 mL), dried (Na2SO4), filtered and evaporated to afford the title product (550 mg, 100%) as a pale brown solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](Cl)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].[NH2:20][C:21]1[CH:29]=[CH:28][C:24]2[NH:25][N:26]=[N:27][C:23]=2[CH:22]=1.Cl.N1C=CC=CC=1>COCCO>[N:25]1[C:24]2[CH:28]=[CH:29][C:21]([NH:20][C:9]3[C:8]4[C:13](=[CH:14][C:5]([O:4][CH2:3][CH2:2][Cl:1])=[C:6]([O:18][CH3:19])[CH:7]=4)[N:12]=[CH:11][C:10]=3[C:15]#[N:16])=[CH:22][C:23]=2[NH:27][N:26]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Reactant: Nc1ccc2[nH]nnc2c1
Agent: Cl
Solvent: COCCO
Solvent: c1ccncc1
Product: COc1cc2c(Nc3ccc4nn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Yield: 81.7 %

Procedure:
The title compound was prepared by the procedure of Example 166 using 0.442 g of 7-(2-chloro-ethoxy)-4-chloro-6-methoxy-quinoline-3-carbonitrile, 0.22 g 5-amino benzotriazole, 0.190 g of pyridine hydrochloride and 15 ml of 2-methoxyethanol to give 0.48 g (82%) of the desired product :mass spectrum (electrospray m/e): M+H=394.8.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:25][O:26][C:27]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[CH:30][C:28]=1[NH2:29].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:28]([NH2:29])=[C:27]([O:26][CH3:25])[CH:33]=3)[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(I)c3c(N)ncnc32)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Temperature: 85 °C
Yield: 91.1 %

Procedure:
A mixture of tert-butyl 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (0.50 g, 11.26 mmol), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.10 g, 12.39 mmol), sodium carbonate (2.90 g, 27.0 mmol) and tetrakis(triphenylphosphine)palladium (0.78 g, 0.67 mmol) in ethylene glycol dimethyl ether (90 mL) and water (45 mL) was heated at 85° C. for 18 hours. The mixture was cooled and evaporated under reduced pressure then partitioned between water (50 mL) and dichloromethane (50 mL). The aqueous layer was extracted further with dichloromethane (2×50 mL) then the combined organic solutions were dried over magnesium sulfate and then filtered. The filtrate was concentrated and purified by flash chromatography on silica gel using dichloromethane/methanol (96:4) as an eluent to provide the title compound (4.51 g, 91%) as a tan solid: 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.04 (s, 1H), 6.98 (d, 1H), 6.76 (d, 1H), 5.06 (bs, 1H), 4.86 (m, 1H), 4.08 (m, 2H), 3.83 (s, 3H), 2.90 (m, 2H), 2.03 (m, 2H), 1.90 (m, 2H), 1.43 (s, 9H); RP-HPLC (Hypersil HS C18 Hypersil HS C18, 5 μm 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05 M ammonium acetate over 10 min, 1 mL/min) tr 9.70 min.
Reaction SMILES: [C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][OH:24])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:1]([N:5]1[C:19]2[C:20]3[C:7]([CH2:8][C@@H:9]4[C@@:14]([O:21][CH3:22])([C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH2:13][C@@H:12]([CH2:23][O:24][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][N:10]4[CH3:25])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Solvent: c1ccncc1
Solvent: O
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C(C)(C)C)c3cccc2c13
Reaction time: 6 h
Yield: 76.6 %

Procedure:
To a solution of 1.8 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-hydroxymethyl-ergoline, prepared as described in Example 2, in 20 ml of pyridine, 2.8 g of tosyl chloride in 15 ml of pyridine were slowly added. After the addition had been completed, the mixture was stirred for about six hours and was then poured into cold water and extracted with dichloromethane. The organic layer was evaporated off and the residue was chromatographed over 18 g of silica gel using dichloromethane with increasing amounts of methanol (from 0 to 4 percent) as the eluant. 2 g of 1-(t-butyl)-10-methoxy-6-methyl-8β-tosyloxymethyl-ergoline were obtained, melting at about 150° to 152° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:36]4[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3s2)CC1
Yield: 26.8 %

Procedure:
5-Chloro-2-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (80 mg) was reacted with 49 mg of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine via General Procedure A. The product was purified by reverse phase HPLC to yield 24.3 mg of 111. MS (Q1) 491.0 (M)+.
Reaction SMILES: Cl.C(O)(=O)C.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([F:24])[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([O:29]CC)=[O:28])=[CH:14]2)[C:10]([CH3:32])=[CH:9][C:8]=1[F:33]>O>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([F:24])[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([CH3:32])=[CH:9][C:8]=1[F:33]
Reactant: CCOC(=O)c1cn(-c2nc(N)c(F)cc2C)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)c(N)nc1-n1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To 800 mg of the mixed solution (1:1) of 4N hydrochloric acid and acetic acid was added 160 mg of ethyl 1-(6-amino-5-fluoro-3-methylpyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture was heated under reflux with stirring for 30 minutes. After adding 0.5 ml of distilled water, the solution was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 145 mg of the title compound as a pale brown powder.