Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:36])[C:15]2[CH:20]=[N:19][C:18](S(C)(=O)=O)=[N:17][C:16]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:12])[CH3:9]>>[CH2:8]([O:10][C:11]([C:13]1[C:14](=[O:36])[C:15]2[CH:20]=[N:19][C:18]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])=[N:17][C:16]=2[N:25]([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[CH2:32][CH2:31][CH2:30]3)[CH:26]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(S(C)(=O)=O)ncc2c1=O
Reactant: CN(C)CCCN
Product: CCOC(=O)c1cn(-c2ccc3c(c2)CCC3)c2nc(NCCCN(C)C)ncc2c1=O

Procedure:
Using the procedure outlined in Example 1(Step F) the title compound was prepared from N1,N1-dimethyl-propane-1,3-diamine (4.6 μL, 0.036 mmol) and 8-indan-5-yl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (from Example 1(Step E), 15 mg, 0.036 mmol). 9.7 mg of 2-(3-dimethylamino-propylamino)-8-indan-5-yl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.46 (s, 1H), 7.34 (d, 1H), 7.23 (s, 1H), 7.13 (d, 1H), 6.77 (br, 1H), (m, 2H), 2.99 (m, 4H), 2.19 (m, 10H), 1.60 (m, 2H), 1.37 (t, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H29N5O3: 436.23 (M+H). Found: 436.4.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]3[CH3:25])=[CH:10][CH:9]=2)[CH2:3]1.C(N(CC)CC)C.[S:33](Cl)([CH3:36])(=[O:35])=[O:34].O>C(Cl)Cl>[CH3:36][S:33]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:23](=[O:24])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[C:15]3[CH3:25])=[CH:10][CH:9]=2)[CH2:3]1)(=[O:35])=[O:34]
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(O)C2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCC(OS(C)(=O)=O)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 112.1 %

Procedure:
3-{(4-[(3-hydroxycyclopentyl)oxy]phenyl}-2-methyl -4(3H)-quinazolinone (520 mg, 1.19 mmol) and triethylamine (0.33 mL, 2.32 mmol) were mixed in methylene chloride and cooled on an ice bath. Mesyl chloride (0.12 mL, 1.55 mmol) was dripped in and stirred for 10 minutes at room temperature. Distilled water was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic phase was washed with distilled water, and dried by anhydrous magnesium sulfate. The residue was concentrated to dryness, and the target compound (553 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:33])[O:12]2)=[O:8])=[CH:4][CH:3]=1.[CH3:34][S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1Br)(=[O:37])=[O:36].C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C@H:11]2[C@H:19]3[N:14]([C:15]4[CH:23]=[CH:22][C:21]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[S:35]([CH3:34])(=[O:37])=[O:36])=[CH:20][C:16]=4[O:17][CH2:18]3)[C:13](=[O:33])[O:12]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc3c(c2)OC[C@H]2[C@H](CNC(=O)c4ccc(Cl)s4)OC(=O)N32)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CS(=O)(=O)c1ccccc1-c1ccc2c(c1)OC[C@H]1[C@H](CNC(=O)c3ccc(Cl)s3)OC(=O)N21
Yield: 35.2 %

Procedure:
Using compound 5-chloro-N-(((3S,3aS)-1-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-yl)methyl)thiophene-2-carboxamide (the product of step (b) in Example 35) (50 mg, 0.102 mmol), o-methylsulfonylbromobenzene (29 mg, 0.122 mmol), tetrakis (triphenylphosphine) palladium (12 mg, 0.010 mmol), and cesium carbonate (66 mg, 0.204 mmol) as starting materials, preparation following the method as described in Example 35 (c) afforded off-white solid 19 mg, yield: 35.2%.
Reaction SMILES: C([O:8][C:9]1[C:34]([O:35][CH3:36])=[CH:33][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[C:11]([F:37])[CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[F:37][C:11]1[C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:30]([CH3:32])[CH3:31])[CH:15]=2)=[CH:33][C:34]([O:35][CH3:36])=[C:9]([OH:8])[CH:10]=1
Reactant: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(Cc2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncccc23)c(F)cc1O
Reaction time: 1 h
Yield: 85.6 %

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (86, 0.831 g, 1.60 mmol) was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL). 10% Palladium on carbon (3.41 g) was added. The reaction was shaken at 50 psi for 1 hour. The reaction was filtered through Celite and washed with methanol. The organic portion was passed through celite several times until a clear solution was obtained. The organic portion was concentrated under reduced pressure to provide the desired compound as an off-white solid (87, 587 mg, 86%).
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13]1.C1([Li])C2C(=CC=CC=2)C=C1.[Br:31][CH2:32][CH2:33]Br.[NH4+].[Cl-]>CCOCC>[Br:31][CH2:32][CH2:33][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]=1
Reactant: BrCCBr
Reactant: C1=Cc2ccccc2C1
Agent: [Cl-]
Agent: [Li]C1C=Cc2ccccc21
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: BrCCC1=CCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 1.6 M n-BuLi solution in hexane (100 mL, 0.16 mol) was added at 0° C. to a solution of indene (18.6 g, MW=116.16, 0.16 mol) in 300 mL of ether. The resulting suspension was allowed to warm to room temperature and stirred for 4 h at the same temperature. Then the indenyl lithium suspension was cooled again to −50° C. and added of a solution of 1,2-dibromoethane (0.24 mol, 21 mL) in 50 mL of ether. The reaction mixture was allowed to warm up slowly to room temperature and stirred overnight. Then it was treated with a saturated aqueous solution of NH4Cl. The organic phase was isolated, evaporated off to dryness and distilled in vacuo, b.p. 110° C./0.5 torr. Yield 21.6 g (60%). The title compound was characterized by NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][NH:21][CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH2:20][N:21]([C:28]([CH:25]2[CH2:27][CH2:26]2)=[O:29])[CH2:22][CH3:23])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1
Product: CCN(Cc1ccc(OC)cc1-c1cc(Cl)cc(CC(=O)OC)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (5-chloro-2′-ethylaminomethyl-5′-methoxy-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:10]2[N:11]=[C:12]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])[N:13]=[C:9]2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=O.[CH3:26][NH2:27]>CCO>[CH3:26][NH:27][C:3]([C:5]1[N:10]2[N:11]=[C:12]([NH:14][C:15]([NH:17][CH2:18][CH3:19])=[O:16])[N:13]=[C:9]2[CH:8]=[C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=1)=[O:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)OC)n2n1
Reactant: CN
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NC)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Ethyl-ureido)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid methyl ester, prepared as in Example 6, (46 mg, 0.14 mmol) was suspended/dissolved in 33% methylamine in EtOH (15 mL), then stirred overnight at room temperature. After this time the reaction mixture was concentrated to a volume of ca 5 mL, then diluted with Et2O (5 mL). The resulting precipitate was isolated by filtration and washed well with Et2O to give the final product mp. >300° C. LCMS (APCI+) 340.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[CH:9][N:8]=1)[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][S:6][C:7]1[CH:12]=[C:11]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=2)[N:10]=[CH:9][N:8]=1)[CH3:2]
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)CSc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CSc1cc(NCc2ccc(Cl)cc2)ncn1

Procedure:
A mixture of the residual oil [(6-chloro-4-pyrimidinylthio)acetic acid ethyl ester], 5.6 g. of p-chlorobenzylamine and 4.26 g. of sodium carbonate in 150 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and was cooled. The precipitate thus formed was collected and recrystallized from ethanol to afford 5.2 g. of product, m.p. 116°-120°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CN(C=O)C>[CH:22]1([CH2:28][NH:29][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCC1CCCCC1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Cyclohexylmethylamine (325 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated which was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (115 mg, 78%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.69 (d, J3=7.80 Hz, 2H), 7.59 (d, J3=8.22 Hz, 2H), 7.50-7.33 (m, 4H), 6.22 (br. s., 1H), 3.31 (t, J3=6.29 Hz, 2H), 1.80-1.53 (m, 6H), 1.31-1.10 (m, 3H), 1.05-0.84 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([O:15][CH2:16][CH2:17][CH3:18])[O:11][CH2:12][CH2:13][CH3:14])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N>C(O)C.[Ni]>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([O:15][CH2:16][CH2:17][CH3:18])[O:11][CH2:12][CH2:13][CH3:14])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCCOC(OCCC)P(=O)(CCC#N)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCCOC(OCCC)P(=O)(CCCN)OCC
Reaction time: 10.5 h

Procedure:
A mixture of 4,35 g of ethyl 2-cyanoethyl(di-n-propyloxymethyl)phosphinate, 10 g of ammonia and 2.3 g of Raney-Nickel in 170 ml of ethanol is hydrogenated for 10.5 hours. The catalyst is filtered off and the solvent is removed by evaporation. The crude oil is purified by distillation to yield ethyl 3-aminopropyl(di-n-propyloxymethyl)phosphinate as a colourless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1([S:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[C:29]1([S:35]([N:38]2[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][C:5]3[CH:6]=[C:7]([NH:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=[C:14]([CH3:22])[CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cc(Nc2cccc(OCCCl)c2)c2ccccc2n1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cccc(OCCN3CCN(S(=O)(=O)c4ccccc4)CC3)c2)c2ccccc2n1
Temperature: 90 °C
Yield: 5.9 %

Procedure:
To a solution of 21 (250 mg, 0.67 mmol) in DMF (5 mL) were sequentially added sodium carbonate (149 mg, 1.41 mmol). and 22 (183 mg, 0.808 mmol). The reaction was placed under a N2 atmosphere and heated at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified via reversed phase HPLC to yield the title compound as a pale yellow solid (20 mg, 6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].CI.[C:13]([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:13])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1ccc(Br)cc1C#N

Procedure:
A mixture of 5-bromo-2-hydroxybenzonitrile (1 g, 5 mmol), MeI (0.85 g, 6 mmol) and K2CO3 (2 g, 15 mmol) in 25 mL of dry CH3CN were heated to refluxed over night. The solvent was evaporated off and the residue was added water. Extracted the mixture with DCM and the organic layer was washed with saturated chloride, dried over Na2SO4. The residue was purified with fast column chromatograph to afford compound 5-bromo-2-methoxybenzonitrile.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[N:22]=[C:21]2[C:17]([NH:18][CH:19]=[N:20]2)=[C:16]([Cl:23])[N:15]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:23][C:16]1[N:15]=[C:14]([NH2:13])[N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[CH2:2][C:3]1[S:4][C:5]2[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1cccc2nc(CBr)sc12
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)c2ncn(Cc3nc4cccc(Cl)c4s3)c2n1
Temperature: 40 °C
Yield: 73.7 %

Procedure:
A mixture of 2-bromomethyl-7-chloro-benzothiazole (60 mg, 0.2286 mmol), 2-amino-6-chloropurine (32 mg, 0.19 mmol), Cs2CO3 (67.86 mg, 0.208 mmol), and DMF (2 ml) was heated to 40° C. for 1 h. The reaction was cooled to r.t. and the solvent was removed on a rotary evaporator. The resulting solid was purified by preparative TLC to give the title compound (50 mg, 0.14 mmol). HPLC Rt: 5.81 min. 1H-NMR (CDCl3): δ 8.0 (s, 1H), 7.95 (d, 1H), 7.48 (t, 1H), 7.43 (d, 1H), 5.69 (s, 2H), 5.17 (s, 2H).
Reaction SMILES: CN[CH2:3][C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.[C-:13]#[N:14].[Na+].C(O)(=O)C>CS(C)=O.O>[OH:10][C:9]1[CH:11]=[CH:12][C:4]([CH2:3][C:13]#[N:14])=[CH:5][C:6]=1[O:7][CH3:8]
Reactant: [C-]#N
Reactant: CNCc1ccc(O)c(OC)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(CC#N)ccc1O
Temperature: 125 °C
Reaction time: 2 h

Procedure:
160.8 g of N-methylvanillylamine and 54 g of sodium cyanide are suspended in 1 liter of dimethylsulphoxide and dissolved by heating to 125°C. At this temperature, a solution of 100 ml of glacial acetic acid in 200 ml of water is added and the mixture is stirred for a further 2 hours under nitrogen at 125°C. It then cooled to 80°C and the dimethylsulphoxide is distilled off in a water-pump vacuum. 900 ml of water are added to the residue which is extracted with 350 ml of chloroform. The chloroform phase is extracted by shaking with water and dried with sodium sulphate. On distilling off the chloroform in vacuo, an oil is obtained, which is cooled and seeded. The crystals formed melt at 53°-54°C (boiling point0.1 :140°-144°C). The yield is 143 g (94% of theory).
Reaction SMILES: Cl[C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14]([NH:22][CH:23]2[CH2:25][CH2:24]2)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.[C:26]([O:30][C:31](=[O:52])[NH:32][C:33]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35][CH2:34]1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:26]([O:30][C:31](=[O:52])[NH:32][C:33]1([C:37]2[CH:38]=[CH:39][C:40]([C:2]3[C:15]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[C:14]([NH:22][CH:23]4[CH2:25][CH2:24]4)[N:5]4[N:6]=[C:7]5[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]5)=[C:4]4[N:3]=3)=[CH:41][CH:42]=2)[CH2:34][CH2:35][CH2:36]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: Fc1ccc2nn3c(NC4CC4)c(-c4ccccc4)c(Cl)nc3c2c1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c5cc(F)ccc5nn4c(NC4CC4)c3-c3ccccc3)cc2)CCC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
300 mg (0.9 mmol) (2-Chloro-9-fluoro-3-phenylpyrimido[1,2-b]indazol-4-yl)-cyclopropylamine, 444.4 mg (1.2 mmol) {1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclobutyl}carbamic acid tert-butyl ester, 1.6 mL aqueous sodium carbonate (10%) and 31.2 mg (0.04 mmol) 1,1 bis(diphenylphosphino)ferrocenedichloropalladium(II) were given in 2.9 mL dimethoxyethane and heated for 40′ in the microwave at 120° C. The reaction mixture was poured on water and ethyl acetate and stirred vigorously for 30 minutes. The organic phase was separated and washed twice with brine. After drying with sodium sulfate the solvent was removed and the crude residue (720 mg) was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]4[CH2:30][CH2:29][CH2:28][O:27]4)[CH:20]=3)[C:15]2=[O:31])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1.[NH:32]1[CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH:10]2[CH2:11][CH2:12][N:8]([C:7]3[CH:6]=[CH:5][C:4]([N:14]4[CH:23]=[CH:22][C:21]5[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@H:26]6[CH2:30][CH2:29][CH2:28][O:27]6)[CH:20]=5)[C:15]4=[O:31])=[CH:3][C:2]=3[F:1])[CH2:9]2)[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: O=C1CCN(c2ccc(-n3ccc4cc(OC[C@H]5CCCO5)ccc4c3=O)cc2F)C1
Product: O=c1c2ccc(OC[C@H]3CCCO3)cc2ccn1-c1ccc(N2CCC(N3CCC3)C2)c(F)c1

Procedure:
2-[3-Fluoro-4-(3-oxo-pyrrolidin-1-yl)-phenyl]-6-[(R)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one was reacted with azetidine according to Method J1. In this way the product was obtained with molecular weight 463.23 (C27H30FN3O3); MS (ESI): 464 (M+H+).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:28]=[CH:29][CH:30]=2)O1>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:29]3[CH:28]=[C:27]([C:31]4[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:26]=[CH:25][CH:30]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Product: COC(C)(OC)c1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Yield: 76 %

Procedure:
3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidine (197 mg, 0.50 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-[7-(1,1-dimethoxyethyl)imidazo[1,2-a]pyrimidin-3-yl]biphenyl-2-carbonitrile (200 mg, 76%) as a white powder: δH (360 MHz, CDCl3) 1.72 (3H, s), 3.30 (6H, s), 7.39 (1H, d, J 7), 7.49-7.73 (6H, m), 7.78-7.84 (2H, m), 7.97 (1H, s), 8.95 (1H, d, J 7); m/z (ES+) 385 (M++H).
Reaction SMILES: O=[CH:2][C:3]1C=CC(O)=C(OC)[CH:4]=1.[CH:12]1[CH:17]=[C:16]([CH2:18]N)C=[C:14]([CH2:20][NH2:21])[CH:13]=1>>[CH3:2][CH2:3][CH2:4][CH2:18][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH2:20][NH2:21]
Reactant: COc1cc(C=O)ccc1O
Reactant: NCc1cccc(CN)c1
Product: CCCCCCCCCCN

Procedure:
according to the general preparation protocol for the reductive alkylation, 30.4 g of vanillin (=4-hydroxy-2-methoxybenzaldehyde) and 13.6 g of MXDA were reacted. There was obtained a clear, orange oil with a viscosity of 62,380 mPa·s at 60° C. and an amine content of 5.0 mmol N/g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1.I[CH2:29][CH:30]1[CH2:34][CH2:33][CH:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:31]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([C:17]1[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:21][CH:22]=1)[CH2:29][CH:30]1[CH2:34][CH2:33][CH:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH2:31]1
Reactant: ICC1CCC(OC2CCCCO2)C1
Reactant: COC(=O)Cc1ccc(S(C)(=O)=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCC(OC2CCCCO2)C1)c1ccc(S(C)(=O)=O)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.1 %

Procedure:
A solution of diisopropylamine (810 μL, 5.78 mmol) in dry tetrahydrofuran (4.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 mL) cooled to −78° C. was treated with a 2.5M solution of n-butyllithium in hexanes (2.3 mL, 5.78 mmol). The reaction mixture was stirred at −78° C. for 30 min and then treated with a solution of (4-methanesulfonyl-phenyl)-acetic acid methyl ester (prepared as in Example 8, 1.10 g, 4.82 mmol) in dry tetrahydrofuran (4.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1.5 mL). The resulting reaction mixture was allowed to stir at −78° C. for 1 h and then the reaction mixture was treated with a solution of 2-(3-iodomethyl-cyclopentyloxy)-tetrahydropyran (prepared as in Example 35, 1.94 g, 6.26 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture was stirred at −78° C. for 10 min and then allowed to warm to 25° C., where it was stirred for 3 d. The reaction mixture was quenched with water (50 mL) and then concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was further diluted with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 7/3 hexanes/ethyl acetate) afforded the 2-(4-methanesulfonyl-phenyl)-3-[3-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (1.07 g, 54%) as a yellow oil: FAB-HRMS m/e calcd for C21H30O6S (M+H)+ 411.1841, found 411.1851.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[O:20]1[CH2:24][CH:21]1[CH2:22]Br.O>CS(C)=O>[O:20]1[CH2:24][CH:21]1[CH2:22][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCC2CO2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 4-hydroxy-1-naphthaldehyde (1 g, 5.8 mmol) in DMSO (20 mL) was added K2CO3(1 g, 7.2 mmol ). The mixture was stirred at room temperature for 30 min, and then 2,3-epoxypropyl bromide (0.96 g, 7 mmol) was added. After stirring for 24 hr, water (100 mL) was added. The mixture was extracted with ethyl acetate (3×80 mL), dried (MgSO4), and concentrated to give a brown solid (1.23 g, 93%).