Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[CH2:6][CH2:7][N:8]([CH2:19][CH2:20][C:21]1[C:29]2[S:28][C:27](=[O:30])[NH:26][C:25]=2[C:24]([OH:31])=[CH:23][CH:22]=1)[C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl.[F:46][C:47]1[CH:48]=[C:49]([CH:53]=[C:54]([F:56])[CH:55]=1)[CH2:50][CH2:51][NH2:52]>C(O)C>[CH:32]1([N:5]([C:1](=[O:4])[CH2:2][CH2:3][NH:52][CH2:51][CH2:50][C:49]2[CH:53]=[C:54]([F:56])[CH:55]=[C:47]([F:46])[CH:48]=2)[CH2:6][CH2:7][N:8]([CH2:19][CH2:20][C:21]2[C:29]3[S:28][C:27](=[O:30])[NH:26][C:25]=3[C:24]([OH:31])=[CH:23][CH:22]=2)[C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: C=CC(=O)N(CCN(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCC1
Reactant: NCCc1cc(F)cc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cc(F)cc(F)c1)C1CCCCC1
Temperature: 25 °C

Procedure:
Benzyl {2-[acryloyl(cyclohexyl)amino]ethyl}[2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate prepared as in Example 12 step i) (0.33 g), triethylamine (0.176 mL) and 3,5-difluorophenethylamine hydrochloride (0.244 g) were stirred in ethanol (3 mL) at 60° C. for 44 h. The mixture was cooled to room temperature, quenched with water (30 mL), extracted with ethyl acetate (50 mL), the organic extracts washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by flash silica chromatography with 10% methanol/dichloromethane as eluent. The pure fractions were evaporated to dryness to afford the sub-title product (0.35 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]#[C:3][CH2:4][N:5]1[C:9]([N:10]2[CH2:15][C@H:14]([NH2:16])[CH2:13][CH2:12][CH2:11]2)=[N:8][C:7]2[N:17]([CH3:35])[C:18]([N:20]([CH2:23][C:24]3[N:25]=[C:26]([CH3:34])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[N:33]=3)[C:21](=[O:22])[C:6]1=2)=[O:19].[C:36]([OH:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(O)(C)C>[CH3:1][C:2]#[C:3][CH2:4][N:5]1[C:9]([N:10]2[CH2:15][C@H:14]([NH2:16])[CH2:13][CH2:12][CH2:11]2)=[N:8][C:7]2[N:17]([CH3:35])[C:18]([N:20]([CH2:23][C:24]3[N:25]=[C:26]([CH3:34])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[N:33]=3)[C:21](=[O:22])[C:6]1=2)=[O:19].[C:36]([O-:44])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccccc1
Agent: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(Cc1nc(C)c3ccccc3n1)c(=O)n2C
Solvent: CC(C)O
Product: O=C([O-])c1ccccc1
Temperature: 25 °C
Reaction time: 7.5 h

Procedure:
A mixture of 2.50 g Linagliptin free base in 20 ml isopropanol was heated to reflux. To the hot suspension 646 mg benzoic acid dissolved in 5 ml isopropanol were added. The mixture was allowed to cool to about 25° C. and further stirred at the same temperature for about 7.5 hours. The solid was isolated by filtration and dried at 40° C. for about 13 hours to obtain 2.94 g crystalline Linagliptin benzoate of WO2010/072776 A1, which was confirmed to be Linagliptin benzoate form I by XRPD.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1.[C:25](O)([CH3:28])([CH3:27])[CH3:26].CN(C)C1C=CN=CN=1>C(Cl)Cl>[CH2:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1
Reactant: CC(C)(C)O
Reactant: O=C(O)C1CCCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 48.2 g of dicyclohexylcarbodiimide in 100 ml of methylene chloride is added dropwise at room temperature with stirring to a solution of 27.7 g (0.2 mol) of 4-cyclohexanecarboxylic acid, 28.9 g of tert-butanol and 24 g of 4-dimethylaminopyrimidine in 200 ml of methylene chloride. The mixture is stirred for 24 hours at room temperature, dicyclohexylurea is removed by filtration, and the product is extracted twice by stirring with water. The organic phase is dried and concentrated. The crude product is purified by distillation on a thin-film evaporator (150°/0.4 mm). This gives 20 g (51.8% of theory) of a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[Cl:30].[Cu](C#N)[C:32]#[N:33].C(OCC)(=O)C>CN(C)C=O>[Cl:30][C:3]1[CH:4]=[C:5]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[C:32]#[N:33]
Reactant: O=S(=O)(c1ccc(Br)c(Cl)c1)N1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(-c4ccc(C(F)(F)F)cc4)ccc32)cc1Cl
Temperature: 200 °C
Yield: 42.1 %

Procedure:
2.48 g 1-(4-bromo-3-chloro-benzenesulfonyl)-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-indole were dissolved in 10 ml dimethylformamide. 2.15 g copper cyanide were added and the resulting mixture stirred under microwave irradiation at 200° C. for thirty minutes. The mixture was diluted by addition of 100 ml ethyl acetate and washed five times with portions of 50 ml saturated ammonium chloride solution. The organic layer was dried over MgSO4 then the solvent was removed in vacuo to obtain 935 mg crude 2-chloro-4-[5-(4-trifluoromethyl-phenyl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile. This material was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([C:23](=[O:37])[N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:11][N:10]=1)(C)(C)C.Cl>CCOC(C)=O>[CH2:30]([N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:23]([C:12]1[C:13]2[C:18](=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(CCN(C)C)Cc3ccccc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc(OC)c2c(CN)ncc(C(=O)N(CCN(C)C)Cc3ccccc3)c2c1
Yield: 100.6 %

Procedure:
As described in example 1, 91 mg of {4-[benzyl-(2-dimethylamino-ethyl)-carbamoyl]-6,8-dimethoxy-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 74 mg (>100%) of 1-aminomethyl-6,8-dimethoxy-isoquinoline-4-carboxylic acid benzyl-(2-dimethylamino-ethyl)-amide MS: APCI (M+H) calc'd for C24H30N4O3+H 423.5; found 423.2.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH3:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1>C(O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([CH:2]=[C:3]([CH2:4][CH3:5])[N:7]=2)[CH:10]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCc1cn2cc(Br)ccc2n1
Temperature: 25 °C
Yield: 64.9 %

Procedure:
5.0 g of 1-bromo-2-butanone was dissolved in 80 ml of ethanol, 5.71 g of 2-amino-5-bromopyridine was added, and the mixture was stirred all night by heating under reflux. After cooling down to room temperature, the solvents were distilled outunder reduced pressure, and ethyl acetated followed by saturated sodium bicarbonate aqueous solution were added. After drying organic layer with anhydrous sodium sulfate, the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer silicagel chromatography (hexane:ethyl acetate=75:25), to obtain 4.82 g of the above compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH2:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Reactant: COCCCBr
Product: COCCCn1c(C(=O)N2CCS(=O)(=O)CC2)cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc21

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 1, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and 1-bromo-3-methoxypropane. The desired product was obtained in a yield of 65% as light yellow foam. MS (m/e): 570.4 (M+H, 70%).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@H:9](/[CH:20]=[CH:21]/[C@@H:22]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:8]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43]CC2C=CC=CC=2)[CH:38]=1)(=[O:4])=[O:3].[OH-].[K+]>CO.[Pd]>[CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14])[C@H:9](/[CH:20]=[CH:21]/[C@@H:22]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:8]1[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([OH:43])[CH:38]=1)(=[O:4])=[O:3]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(OCc3ccccc3)c2)[C@@H](COS(C)(=O)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](Cc2cccc(O)c2)[C@@H](COS(C)(=O)=O)C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 127.2 %

Procedure:
A solution of ((1S,2S,3R,4R)-2-(3-(benzyloxy)benzyl)-4-(tert-butyldimethylsilyoxy)-3-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)cyclopentyl)methyl methanesulfonate (45 g, 0.06 mol) in dry methanol (450 ml) was treated with potassium hydroxide (9.72 g, 0.18 mol), then with 5% Pd/C (13.5 g, 30% wt) under hydrogen for 2 hr. Then, the reaction mixture was filtered with celite pad. The filtrate was concentrated to obtain crude product (50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([C@H:12]([CH3:25])[N:13]([C:16]([C:18]4[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=4)=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CC1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1cccc(O)c1
Solvent: ClC(Cl)Cl
Product: C[C@H]1c2ccccc2-c2ccc(Cl)cc2N1C(=O)c1cccc(O)c1

Procedure:
The enantiomers of 3-[(3-chloro-6-methylphenanthridin-5(6H)-yl)carbonyl]phenol (367 mg, 1.05 mmol) were separated by automated, preparative, normal phase, chiral chromatography on a Chiralpak AD (20 mm×250 mm) column eluting with 100% ethanol at a flow rate of 10 mL/min. After combination of fractions and evaporation of the solvent in vacuo, one peak (99.9%) with a retention time of 9.771 minutes was isolated as a white solid (135 mg, 74% based upon a 1:1 ratio of enantiomers with a theoretical maximum amount of 183.5 mg). [α]D25=+440° (c=g/mL, CHCl3);1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=6.73 Hz, 3 H) 5.64 (d, J=6.21 Hz, 1H) 6.69 (d, J=7.50 Hz, 1H) 6.72 (s, 1 H) 6.83 (dd, J=2.59, 1.03 Hz, 1 H) 6.85 (m, 1 H) 6.92 (s, 1 H) 7.16 (t, J=7.89 Hz, 1 H) 7.28 (dd, J=8.41, 2.20 Hz, 1 H) 7.39 (m, 2 H) 7.45 (m, 1 H) 7.98 (d, J=8.54 Hz, 2 H); MS (ESI) m/z 350/352 ([M+H]+); MS (ESI) m/z 348/350 ([M−H]−); HRMS: calcd for C21H16ClNO2, 349.0870 (M), 350.09424 ([M+H]+); found (ESI+), 350.09345.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C@H:27]2[C@@H:36]([C:37]([OH:39])=O)[C:35]3[C:30](=[CH:31][C:32]([O:42][CH3:43])=[C:33]([O:40][CH3:41])[CH:34]=3)[C:29](=[O:44])[N:28]2[CH3:45])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([O:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]2[C:37](=[O:39])[C:36]3[C:35]4[C:30](=[CH:31][C:32]([O:42][CH3:43])=[C:33]([O:40][CH3:41])[CH:34]=4)[C:29](=[O:44])[N:28]([CH3:45])[C:27]=3[C:15]=2[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc2c(cc1OC)[C@H](C(=O)O)[C@H](c1ccc(OCc3ccccc3)c(OCc3ccccc3)c1)N(C)C2=O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2c3c(n(C)c(=O)c2cc1OC)-c1cc(OCc2ccccc2)c(OCc2ccccc2)cc1C3=O
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
Thionyl chloride (15 mL) was added with stirring to the cis acid 12h (1.2 g, 2.2 mmol). The result was an orange mixture that became dark red within 15 min. After 6 h, the reaction mixture was diluted with benzene (25 mL) and evaporated to dryness. Chloroform (7 mL) was added to the purple solid and the solid was collected and washed with ether to give a light purple solid (0.75 g, 64%): mp 238-240° C.; IR (thin film) 3027, 2963, 1685, 1649, 1493, 1458, 1252, 1203, 1088, 1014 cm−1; 1H NMR (CDCl3, 300 MHz) δ7.96 (s, 1H), 7.62 (s, 1H), 7.38 (m, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 5.23 (d, 4H, J=5.2 Hz), 4.02 (s, 3H) 3.95 (s, 3H), 3.81 (s, 3H); CIMS m/z (relative intensity) 534 (MH+, 22). Anal. Calcd for C33H27NO6: C, H, N.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:10])[CH3:9])=[N:6][CH:7]=1.OB(O)[C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([NH:22][C:23]2[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=2)[CH:21]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[OH:10][CH:8]([C:5]1[N:6]=[CH:7][C:2]([C:13]2[CH:14]=[C:15]([CH:19]=[C:20]([NH:22][C:23]3[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=3)[CH:21]=2)[C:16]([OH:18])=[O:17])=[CH:3][CH:4]=1)[CH3:9]
Reactant: O=C(O)c1cc(Nc2nccc(C(F)(F)F)n2)cc(B(O)O)c1
Reactant: CC(O)c1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(O)c1ccc(-c2cc(Nc3nccc(C(F)(F)F)n3)cc(C(=O)O)c2)cn1
Yield: 72.2 %

Procedure:
A mixture of 1-(5-bromopyridin-2-yl)ethanol (40.3 mg, 0.199 mmol), 3-(dihydroxyboranyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoic acid (31.8 mg, 0.072 mmol), PdCl2(dppf) (11.9 mg, 0.016 mmol), sodium carbonate (2 M, 0.15 mL, 0.300 mmol) and DMF (2 mL) was flushed and purged with Ar(g) (3×) and irradiated in a microwave reactor for 15 minutes at 120° C. The mixture was filtered and was directly purified by reverse phase HPLC to afford 3-[6-(1-hydroxyethyl)pyridin-3-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}benzoic acid (26.7 mg, 0.052 mmol, 71.4%). MS APCI C19H16F3N4O3 [M+H]+ 405. found 405. 1H NMR (500 MHz, DMSO-d6) δ13.1 (s, 1H), 10.54 (s, 1H), 8.88 (d, J=5.1 Hz, 1H), 8.77 (s, 1H), 8.38 (d, J=7.9 Hz, 2H), 8.15 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.34 (d, J=5.1 Hz, 1H), 4.82 (q, J=6.0 Hz, 1H), 1.41 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH2:20]2>>[Br:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH2:20]2
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: Brc1cccc2c1CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2c(Br)cccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Bromo-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[O-]S([O-])(=O)=O.[Mg+2].[CH:14]1[C:19]([CH:20]=O)=[CH:18][C:17]2[O:22][CH2:23][O:24][C:16]=2[CH:15]=1>C(Cl)(Cl)Cl.O>[CH2:23]1[O:24][C:16]2[CH:15]=[CH:14][C:19]([CH:20]=[N:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])=[CH:18][C:17]=2[O:22]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(CN)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(CN=Cc1ccc2c(c1)OCO2)OC
Temperature: 25 °C
Yield: 100 %

Procedure:
Aminoacetaldehyde dimethylacetal (7.10 g, 0.0666 mol) was dissolved in chloroform (50 mL) and MgSO4 (12 g) was added. Then piperonal (10b, 10.10 g, 0.0666 mol) was added and the mixture was stirred at room temperature. After 24 h there still was unreacted piperonal in the reaction mixture and more amine (6.00 g) was added. The reaction mixture was stirred again at room temperature for 24 h and since there still was some piperonal present more amine (6.00 g) was added again. After stirring the reaction mixture for another 24 h at room temperature the imine was isolated. The reaction mixture was diluted with water (300 mL) and the organic layer was washed with water 200 mL×2, brine (200 mL) dried Na2SO4 and concentrated to provide the pure imine as a yellow oil (15.80 g, 100%). 1H NMR (300 MHz, CDCl3) δ 8.13 (s, 1H), 7.33 (s, 1H), 7.07 (d, J=8.10 Hz, 1H), 6.78 (d, J=8.10 Hz, 1H), 5.96 (s, 2H), 4.62 (t, J=5.4 Hz, 1H), 3.70 (d, J=4.2, 2H), 3.83 (s, 6H).
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)(=O)=O.[NH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CN1CCCC1=O>C(OCC)(=O)C.O>[O:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[CH:12][S:11][C:9]=3[N:10]=2)[CH2:16][CH2:17]1
Reactant: NC1CCOCC1
Reactant: CS(=O)(=O)c1ncc2ccsc2n1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: c1cc2cnc(NC3CCOCC3)nc2s1
Temperature: 100 °C
Reaction time: 7 h
Yield: 72.9 %

Procedure:
A mixture of 2-methanesulfonyl-thieno[2,3-d]pyrimidine (1.58 g, 7.37 mmol), 4-aminotetrahydropyran (2.24 g, 3 eq) and 1-methyl-2-pyrolidinone (2 mL) was heated to 100° C. with stirring for about 7 hours and continued heating at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (180 mL)/water (60 mL). The layers were separated, and the organic layer was washed successively with water (4×60 mL) and brine (1×60 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated to give 1.7 g of the crude product. Purification by column chromatography on silica gel eluting with 25% ethyl acetate in hexanes afforded the title compound as a white powder (1.264 g) ((M+H)+=236, M.P.=127.0–130.0° C.).
Reaction SMILES: Cl.[N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[NH:4][CH:3]=1.C(N(CC)CC)C.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[C:22]1([C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:2]2[C:6]3[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=3[N:4]=[CH:3]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1ccc2nc[nH]c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2c(c1)ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.7 %

Procedure:
In dichloromethane (15 ml), methyl 5-benzimidazolecarboxylate hydrochloride (1.00 g) was suspended. To the resulting suspension, triethylamine (1.50 ml) and triphenylmethyl chloride (1.50 g) were added, followed by stirring at room temperature for 3 hours. The reaction mixture was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (hexane:ethyl acetate=2:1), whereby title compound (2.10 g, quant.) was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[C:31]([OH:32])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=5[F:34])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:35])[C:12]=2[C@H:36]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:37]([O:39][CH3:40])=[O:38])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].C(O[C:51]1(C)[CH2:56][CH2:55]N(C2N3C=C(C4C=C(C5C=C(C)C=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)[CH2:53][CH2:52]1)C=C>>[C:42]([O:41][C@@H:36]([C:12]1[C:13]([CH3:35])=[CH:14][C:15]2[N:16]([CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:31]([O:32][C@H:56]([CH2:51][CH:52]=[CH2:53])[CH3:55])=[CH:30][C:29]([CH3:33])=[CH:28][C:27]=4[F:34])[CH:21]=3)[N:19]=2)[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:46])([O:4][CH2:1][CH:2]=[CH2:3])[CH2:10][CH2:9]1)[C:37]([O:39][CH3:40])=[O:38])([CH3:45])([CH3:44])[CH3:43]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(O)cc(C)cc5F)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(F)cc(C)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 90 %

Procedure:
Prepared in 90% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-fluoro-6′-hydroxy-4′-methyl-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-7-methyl-2-(5′-methyl-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 698.35.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([CH3:23])=[C:5]([C:9]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2F)(=[O:15])=[O:14])=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32]>C(#N)C>[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH:37][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:13]([NH:12][C:9]1[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:23])[C:3]([CH2:1][CH3:2])=[CH:11][CH:10]=1)(=[O:15])=[O:14])[CH3:32]
Reactant: CCc1ccc(NS(=O)(=O)c2ccccc2F)c(C(=O)O)c1C
Reactant: CCN(CC)CCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCc1ccc(NS(=O)(=O)c2ccccc2NCCCN(CC)CC)c(C(=O)O)c1C
Yield: 10.8 %

Procedure:
A solution of Example 230C (40 mg, 0.12 mmol), triethylamine (0.1 mL), and N,N-diethyl-1,3-propanediamine (0.1 mL) in acetonitrile (1.0 mL) was heated to 200° C. for 1 hour on a Personal Chemistry microwave instrument. The mixture was then purified by reverse phase HPLC to provide the desired product (5.8 mg, 10.8%). 1H NMR (DMSO-d6) δ 1.07 (t, 3H), 1.12 (t, 6H), 2.19 (s, 3H), 2.53 (q, 2H), 3.05-3.12 (m, 8H), 6.02 (br s, 1H), 6.62-6.66 (m, 2H), 6.84 (d, 1H), 7.03 (d, 1H), 7.40 (t, 1H), 7.52 (d, 1H), 8.98 (br s, 1H), 9.50 (br s, 1H); MS (ESI(+)) m/e 448 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>Cl.C(O)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: Cl
Solvent: CCO
Product: CC(=O)N1CCN(c2ncc3c(=O)c(C(=O)O)c[nH]c3n2)CC1
Temperature: 120 °C
Yield: 54.4 %

Procedure:
A suspension of ethyl 5,8-dihydro-2-(4-acetyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (20 g) in a mixture of 4% hydrochloric acid (60 ml) and ethanol (20 ml) was refluxed at 120° C. for 1.5 hours. After cooling, the precipitate was collected, washed with water and then with hot water, and dissolved in a 10% sodium hydroxide solution. The insoluble material was filtered off and the filtrate was acidified with diluted hydrochloric acid. The resulting precipitate was collected and recrystallized from dimethyl sulfoxide to give 5,8-dihydro-2-(4-acetyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid (10 g). m.p. 298°-300° C.