Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:27]=[CH:26][C:9]([CH2:10][NH:11][C:12]([C:14]2[CH:15]=[C:16]3[CH2:22][NH:21][C@@H:20]([CH:23]([CH3:25])[CH3:24])[C:17]3=[N:18][CH:19]=2)=[O:13])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[C:35]([C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)#[N:36]>C(Cl)Cl>[C:35]([C:37]1[CH:38]=[CH:39][C:40]([S:43]([N:21]2[CH2:22][C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:9]4[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:27][CH:26]=4)=[O:13])[CH:15]=3)[C@@H:20]2[CH:23]([CH3:24])[CH3:25])(=[O:45])=[O:44])=[CH:41][CH:42]=1)#[N:36]
Reactant: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN[C@H]3C(C)C)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(CNC(=O)c2cnc3c(c2)CN(S(=O)(=O)c2ccc(C#N)cc2)[C@H]3C(C)C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.8 %

Procedure:
To a solution of (S)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide (6.9 mg, 17.8 μmol) in CH2Cl2 (600 μL) was added triethylamine (5.0 μL, 36.6 μmol) and 4-cyanobenzenesulfonyl chloride (5.4 mg, 26.8 μmol). The mixture was stirred at rt for 15 h, at which point it was quenched with saturated aqueous sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC to yield 4.9 mg of (S)-6-((4-cyanophenyl)sulfonyl)-N-(4-(ethylsulfonyl)benzyl)-7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxamide as an HCl salt (13, 46%). LC-MS tR=0.84 min in 1 min chromatography, MS (ESI) m/z 553.5 [M+H]+. 1H NMR (CD3OD, 400 MHz): δ 8.85 (d, J=2.0 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H), 8.03 (dd, J=2.0 Hz, 8.8 Hz, 2H), 7.86 (m, 4H), 7.60 (d, J=8.4 Hz, 2H), 4.93 (m, 2H), 4.73 (dt, J=1.2 Hz, 16.4 Hz, 1H), 4.66 (s, 2H), 3.19 (q, J=7.6 Hz, 2H), 2.41-2.32 (m, 1H), 1.20 (t, J=7.6 Hz, 3H), 1.00 (d, J=7.2 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([OH:12])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.N1C=CN=C1.FC(F)(F)S(O[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])(=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])[CH:11]=1)[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)cc(O)c2n1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 13 h
Yield: 98.1 %

Procedure:
6-fluoro-2-methylquinolin-8-ol (19.0 g, 107 mmol) was dissolved in methylene chloride (300 mL) and treated with 1H-imidazole (10.9 g, 160 mmol) and triisopropylsilyl trifluoromethanesulfonate (33.1 mL, 123 mmol). The reaction was stirred at ambient temperature for 13 hours. The reaction mixture was quenched with saturated NH4Cl and separated. The organic layer was washed twice with saturated NH4Cl, dried over Na2SO4 and concentrated in vacuo to provide the desired product (35 g).
Reaction SMILES: [NH2:1][N:2]1[CH:7]=[N:6][CH:5]=[CH:4][NH:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:1][N:2]2[CH:7]=[N:6][CH:5]=[CH:4][NH:3]2)=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1ccc(F)cc1
Reactant: NN1C=NC=CN1
Product: N#Cc1ccc(NN2C=NC=CN2)cc1

Procedure:
Starting compounds: 2-amino-1,2,4-triazine and 4-fluorobenzonitrile
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[F:23][C:24]([F:43])([F:42])[CH2:25][O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1.Br[CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53]>>[F:43][C:24]([F:42])([F:23])[CH2:25][O:26][C:27]1[N:28]=[C:29]([N:36]2[CH2:40][CH2:39][C@H:38]([OH:41])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=3[C:52]([F:53])([F:54])[F:55])[N:35]=2)[N:32]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3[nH]nnc23)C1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: O[C@H]1CCN(c2nc(OCC(F)(F)F)nc3nn(Cc4ccccc4C(F)(F)F)nc23)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from (S)-1-[5-(2,2,2-Trifluoro-ethoxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol and 1-(bromomethyl)-2-(trifluoromethyl)benzene. MS (m/e): 463.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](O)=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:22])=O>CN(C=O)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([Cl:22])=[O:14])[C:10]([CH3:16])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(C)n2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2cc(C(=O)Cl)c(C)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
According to Scheme 2, Step 2: To a solution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carboxylic acid (37.8 mmol, 9.30 g) and five drops of DMF in DCM (94 mL) was added oxalyl chloride (76 mmol, 6.66 mL) dropwise, at 0° C. The reaction mixture was allowed to warm up to room temperature and was stirred for 3 hours. After concentration, the residue was treated with toluene and was co-evaporated to dryness to yield 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride. To a solution of 1-(4-methoxybenzyl)-3-methyl-1H-pyrazole-4-carbonyl chloride (37.8 mmol) in acetonitrile (94 mL) was added a solution of TMSCHN2 (41.5 mmol, 83.0 mL) dropwise, at 0° C., and then the reaction mixture was allowed to warm up to room temperature and was stirred overnight. After cooling the reaction mixture to −10° C., HBr 48% (14.8 mL) was added dropwise and the reaction mixture was stirred for 2 hours at −10° C. At 0° C., 10% NaOH solution was added to the reaction mixture to reach pH=7. The reaction mixture was diluted with water and EtOAc and the aqueous phase was extracted with EtOAc. The organic phase was dried over MgSO4, was filtered and was concentrated under reduced pressure to yield 2-bromo-1-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)ethanone (30.6 mmol, 9.90 g, 81%) which was used without any purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[H-].[Na+]>CO.C(OCC)(=O)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[CH:6][CH:7]=1
Reactant: BrCCc1ccc(Br)nc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCCN1CCc1ccc(Br)nc1
Temperature: 100 °C
Yield: 75.5 %

Procedure:
To a mixture of dibromide 290 (1.7 g, 6.4 mmol) in 2-pyrrolidone (10 mL, 130 mmol) at room temperature was added sodium hydride, 40% dispersion in mineral oil (1.16 g, 19.3 mmol). This reaction mixture was then heated to 100° C. for 2 h, then cooled to RT and partitioned between water and ethyl acetate. The organic phase was collected, washed with water, saturated aqueous ammonium chloride, and brine. It was then dried (anhydrous MgSO4), filtered and concentrated. Silica gel chromatography (10% methanol/ethyl acetate) gave title compound 291 (1.3 g, 75% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.17-8.16 (m, 1H); 7.42-7.37 (m, 2H); 3.49 (t, J=7.4, 2H); 3.28 (t, J=6.9, 2H); 2.79 (t, J=7.2, 2H); 2.30 (t, J=7.8, 2H); 1.95 (quintet, 7.6, 2H). MS (M+H): 269.1, 271.1
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:17]([Li])CCC.IC>C1COCC1>[O:4]=[C:3]([CH2:5][CH3:17])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6]
Reactant: CC(=O)CC(=O)OCc1ccccc1
Reactant: [Li]CCCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Following the procedure of Weiler, J. Am. Chem. Soc. 1974, 96, 1082, benzyl acetoacetate, 7.68 g (40 mmol) was added dropwise to a 0° C. suspension of sodium hydride (2.1 g of 50% dispersion, 42 mmol) in THF (100 mL). After stirring for 10 minutes n-butyl lithium (16 mL of 2.5 M in hexane) was added and the mixture was aged for an additional 10 minutes. At this time iodomethane (2.74 mL, 44 mmol) in THF (4 mL) was added dropwise and the mixture aged 1 hour while slowly warming to room temperature. Work-up was achieved by quenching at 0° C. with 1N HCl, extracting with ether, washing the ether with aqueous NaHCO3, brine, and drying with MgSO4. Removal of the solvent yielded benzyl 3-oxopentanoate.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:14]3[CH:15]=[CH:16][O:12][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccoc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccoc1
Yield: 49.6 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with 3-furaldehyde (1.04 mL, 11.9 mmol) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-furan-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 1.45 g, 55%)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:47]1[CH2:52][CH2:51][O:50][CH2:49][CH:48]1[C:53]1[C:61]2[S:60][C:59]([NH2:62])=[N:58][C:57]=2[C:56]([O:63][CH3:64])=[CH:55][CH:54]=1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([NH:62][C:59]1[S:60][C:61]2[C:53]([CH:48]3[CH2:49][O:50][CH2:51][CH2:52][O:47]3)=[CH:54][CH:55]=[C:56]([O:63][CH3:64])[C:57]=2[N:58]=1)=[O:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(C(=O)O)ccn1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(C(C)(C)C)c3)nc12

Procedure:
From 2-tert-butyl-isonicotinic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (±)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. ES-MS m/e (%): 428 (M+H+, 100).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1C([N:9]1[CH2:15][CH:14]2[CH:11]([CH2:12][NH:13]2)[CH2:10]1)=O.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([N:32]2[N:36]=[CH:35][CH:34]=[N:33]2)=[C:27]([CH:31]=1)[C:28]([OH:30])=O.C1(C2C=CC=CC=2)C(C(O)=O)=CC=CC=1>>[CH:11]12[CH2:12][NH:13][CH:14]1[CH2:15][N:9]([C:28]([C:27]1[CH:31]=[C:23]([CH3:22])[CH:24]=[CH:25][C:26]=1[N:32]1[N:36]=[CH:35][CH:34]=[N:33]1)=[O:30])[CH2:10]2
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNC2C1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Agent: O=C(O)c1ccccc1-c1ccccc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CNC3C2)c1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 19, substituting 5-methyl-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 59) for biphenyl-2-carboxylic acid. MS (ESI) mass calcd. for C15H17N5O, 283.33; m/z found, 284.2 [M+H]+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl:8][C:9]1[C:17]2[O:16][CH:15](/[C:18](=[N:22]\[OH:23])/[O:19][CH2:20][CH3:21])[CH2:14][C:13]=2[CH:12]=[C:11]([C:24](=[O:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[C:10]=1[OH:33]>>[C:1]([O:23]/[N:22]=[C:18](\[CH:15]1[CH2:14][C:13]2[CH:12]=[C:11]([C:24](=[O:32])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:10]([OH:33])=[C:9]([Cl:8])[C:17]=2[O:16]1)/[O:19][CH2:20][CH3:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCO/C(=N/O)C1Cc2cc(C(=O)c3ccccc3F)c(O)c(Cl)c2O1
Product: CCO/C(=N/OC(C)=O)C1Cc2cc(C(=O)c3ccccc3F)c(O)c(Cl)c2O1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To acetic anhydride (8 ml.) was added (8h) (400 mg., 1.06 mmole). After stirring for 1 hour at 90° C. the mixture was left to stand at room temperature for 18 hours, then evaporated to dryness under high vacuum. The product, an oil, was triturated in absolute ethanol, giving crystalline (9h), m.p. 111°-112° C. in 58.4% yield. Analysis (C20H17ClFNO6) C,H,N.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([S:13]([C:16]2([C:21]#[N:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([S:13]([C:16]2([CH2:21][NH2:22])[CH2:20][CH2:19][CH2:18][CH2:17]2)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CC1(S(=O)(=O)c2ccccc2)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCC1(S(=O)(=O)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.8 %

Procedure:
194 mg (5.1 mmol) of lithium aluminum hydride is added to a solution of 1 g (4.2 mmol) of 1-benzenesulfonyl-cyclopentanecarbonitrile in 20 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature (RT) for 20 h. It is then hydrolyzed with 194 μl of water, 194 μl of a 15% soda solution and then 582 μl of water, stirred for 5 minutes, then filtered. The filtrate is evaporated and the residue is chromatographed on silica gel (dichloromethane then dichloromethane/methanol, 90/10, v/v). 420 mg of C-(1-benzenesulfonyl-cyclopentyl)-methylamine is obtained in the form of a colorless oil. (Yield=42%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:36][N:37]([CH3:41])[C:38](Cl)=[O:39]>>[CH3:36][N:37]([CH3:41])[C:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)=[O:39]
Reactant: CN(C)C(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N(C)C)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available dimethylcarbamyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=549 by positive ion CI
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39].[H-].[Na+].Cl[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1.CN(C=O)C>C1COCC1>[N:44]1[CH:45]=[CH:46][CH:47]=[N:48][C:43]=1[O:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=[C:7]([NH:17][S:18](=[O:30])(=[O:29])[NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=2)[C:6]=1[O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[O:38][CH3:39]
Reactant: Clc1ncccn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)Nc2ccc(C(C)C)cc2)nc(-c2ccncc2)nc1OCCOc1ncccn1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
4-i-Propyl-phenyl sulfamic acid-[6-(2-hydroxy-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (60 mg, Example 3) was dissolved in THF (8 ml) and sodium hydride (14 mg, 60% dispersion in mineral oil) was added and stirring continued for 10 min. 2-Chloro-pyrimidine (22 mg) was added and the mixture was heated to 60° C. for 90 min. DMF (0.5 ml) was added and the solution was stirred at r.t. for 48 h. The solvents were evaporated, water (12 ml) and a 10/solution of citric acid was added until the pH was 3. The precipitate was filtered off and washed with water and purified by recrystallization from diethyl ether to give 4-i-propyl-phenyl sulfamic acid-[6-[2-(pyrimidin-2-yloxy)-ethoxy]-5-(o-methoxyphenoxy)-2-(4-pyridyl)-pyrimidin-4-yl]-amide (50 mg). tR=4.80 min, (LC); [M+H]+=630.91 (ES+).
Reaction SMILES: C([O:3][C:4]([C:6]1([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)[CH2:11][CH2:10][C:9]([F:13])([F:12])[CH2:8][CH2:7]1)=O)C.[NH3:20]>CO>[F:12][C:9]1([F:13])[CH2:10][CH2:11][C:6]([N:14]2[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]2)([C:4]([NH2:20])=[O:3])[CH2:7][CH2:8]1
Reactant: N
Reactant: CCOC(=O)C1(n2cnc(C)c2)CCC(F)(F)CC1
Solvent: CO
Product: Cc1cn(C2(C(N)=O)CCC(F)(F)CC2)cn1
Reaction time: 72 h
Yield: 45 %

Procedure:
4,4-Difluoro-1-(4-methyl-imidazol-1-yl)-cyclohexanecarboxylic acid ethyl ester (199 mg, 0.731 mmol was dissolved in 7 M ammonia in methanol (5 mL) and stirred for 72 hours. The sample was concentrated and the residue was purified by flash column chromatography on silica gel (eluding w a gradient elution from heptane to AcOEt to 5% Et3N/10% MeOH185% AcOEt) to give the title compound (84 mg, 45%) 1H NMR (CDCl3 500 MHz): 6 ppm 7.64 (s, 1H), 6.82 (s, 1H), 5.17 (m, 2H), 2.68 (m, 2H), 2.41 (m, 2H), 2.30 (s, 3H), 2.23 (m, 2H), 1.85 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1.[CH2:12](OC(OCC)OCC)C.C(OC(=O)C)(=O)C>>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]2[N:9]([CH3:12])[CH:10]=[N:11][C:4]=2[CH:3]=1
Reactant: CNc1c(N)cc(Br)nc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: Cn1cnc2cc(Br)nc(Cl)c21
Temperature: 155 °C

Procedure:
The above crude diamine 2.59-A was dissolved in a mixture of triethylorthoformate:Acetic anhydride (1:1, 9 mL). The reaction mixture was heated to 155° C. for 1 h, cooled to rt and then evaporated. The residue was dissolved in 2.5M NaOH (20 mL) and heated at 50° C. 45 min. The resulting solution was cooled to rt, neutralized with AcOH, and cooled to 0° C. The precipitate was filtered to give 6-bromo-4-chloro-3-methyl-3H-imidazo[4,5-c]pyridine 2.60.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[N:16]=1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1>CN(C=O)C>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([OH:37])[CH2:32][CH2:33][N:34]([C:11]3[CH:12]=[CH:13][C:14]4[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=4)[N:16]=3)[CH2:35][CH2:36]2)=[CH:27][CH:26]=1
Reactant: Oc1ccc(C2(O)CCNCC2)cc1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Oc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
DIPEA (1.174 mL, 6.74 mmol) was added to 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (1 g, 4.49 mmol) and 4-(4-hydroxyphenyl)piperidin-4-ol (0.955 g, 4.94 mmol) in DMF (10 mL). The resulting solution was stirred at 80° C. for 1 hour. The reaction mixture was cooled to room temperature then evaporated to dryness. The residues were triturated with water and the resulting solid collected by filtration, washed with further water followed by ether, then dried under vacuum to afford 4-(4-hydroxyphenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (1.680 g, 99%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[NH:13][C:12](=[O:14])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:21][O+](C)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[N:13]=[C:12]([O:14][CH3:21])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: CC1(c2cccc(Br)c2)COCC(=O)N1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC1=NC(C)(c2cccc(Br)c2)COC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 98.9 %

Procedure:
In a vacuum dried flask under an argon atmosphere, a solution of (RS)-5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (3.0 g, 11.1 mmol) in dichloromethane (145 ml) was treated with trimethyloxonium tetrafluoroborate (2.594 g, 17 mmol). The reaction mixture was stirred at room temperature for 17 hours. For the workup, the incomplete reaction was extracted with a saturated solution of sodium hydrogen-carbonate (70 ml). The organic layer was dried over sodium sulfate and evaporated. There were obtained 3.12 g of the title compound as light yellow oil containing about 17% of the starting lactam. Mass (calculated) C12H14BrNO2 [284.16]; (found) [M+H]+=284, [M+2-H]+=286.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][OH:22])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:15]3[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][O:22][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:16]3)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(N1CCCC(CO)C1)C1(c2ccc(Cl)cc2)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCCC2)C1
Reaction time: 1 h

Procedure:
To a solution of [1-(4-chloro-phenyl)-cyclopentyl]-(3-hydroxymethyl-piperidin-1-yl)-methanone (0.5 g, 1.55 mmol) in dichloromethane (9.5 mL) at room temperature was added iPr2NEt (0.5 g, 3.9 mmol) followed by MsCl (0.214 g, 1.86 mmol). The reaction mixture was allowed to stir for one hour before concentrating and purifying the resulting residue by silica gel chromatography (gradient 2.5-100% EtOAc in hexane). The desired compound was obtained as an oil (0.345 g, 56%). 13C (100 MHz, CDCl3, partial) δ 174.0, 144.0, 131.8, 128.8, 126.5, 70.8, 58.1, 35.3, 26.5, 24.9. 1H (300 MHz, CDCl3) δ 7.26-7.24 (m, 2H), 7.13-7.10 (m, 2H), 4.61-1.86 (m, 19H), 1.67 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:7](I)[CH:6]=1.C(N(CC)CC)C.[Cl:25][CH2:26][CH2:27][CH2:28][C:29]#[CH:30]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:1][O:2][C:3](=[O:17])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][Cl:25])[CH:6]=1
Reactant: C#CCCCCl
Reactant: COC(=O)Nc1ccc(OC(=O)OC)cc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(OC(=O)OC)cc1C#CCCCCl
Temperature: 70 °C

Procedure:
Carbonic acid 3-iodo-4-methoxycarbonylamino-phenyl ester methyl ester (28.0 g, 79.75 mmol) was dissolved in acetonitrile (350 mL). Triethylamine (22.2mL, 160 mmol), Copper (I) iodide (300 mg, 1.58 mmol), bis(triphenylphosphine)palladium (II) chloride (1.12 g, 1.6 mmol) and 5-chloro-1-pentyne (10.0 mL, 95.54 mmol) were added and the mixture heated 3 h at 70° C. The reaction was cooled and partitioned between ethyl acetate (100 mL) and IM pH4 phosphate buffer (100 mL). The phases were separated, the aqueous phase extracted with ethyl acetate and the combined organic phases washed with 10% sodium thiosulfate solution, brine, dried over sodium sulfate and evaporated. The orange/brown residue (23.5 g, 90%) was used without further purification. (A small sample was purified by column chromatography on silica gel (5:1 hexane/ethyl acetate) for analytical purposes). ISP-MS: m/e=326.3 ([M−H]+)