Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[Cl:8][C:9]1[C:10]([CH2:23]O)=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21].CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:8][C:9]1[C:10]([CH2:23][C:1]#[N:3])=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:19][N:20]([CH3:22])[CH3:21]
Reactant: CCN(CC)CC
Reactant: CN(C)Cc1cccc2cc(Cl)c(CO)cc12
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CN(C)Cc1cccc2cc(Cl)c(CC#N)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.4 %

Procedure:
Triethylamine (0.12 ml, 0.87 mmol, 2.0 equiv) was added to a solution of (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-methanol (109 mg, 0.44 mmol) in CH2Cl2 (1.5 ml). At −25° C., a solution of methanesulfonyl chloride (0.05 ml, 0.66 mmol, 1.5 equiv) in CH2Cl2 (1.5 ml) was then added dropwise. After 15 minutes at 0° C., cold water (4° C., 10 ml) was added, and the mixture was extracted with CH2Cl2 (2×40 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude mesylate was dissolved in N,N-dimethylformamide (2 ml) and treated at 0° C. with potassium cyanide (39 mg, 0.60 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 2 hours, until TLC analysis indicated complete conversion. After dilution with water (50 ml), the mixture was extracted with CH2Cl2 (2×200 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (hexane/EtOAc 100:0 to 80:20) afforded the title compound (54 mg, 48%, mixture of 2 regioisomers). The regioisomers could be separated by preparative HPLC. Data for (3-chloro-8-dimethylaminomethyl-naphthalen-2-yl)-acetonitrile: 1H NMR (400 MHz, CDCl3): δ=8.20 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.72 (d, J=6.6 Hz, 1H), 7.55 (dd, J=8.4/6.6 Hz, 1H), 4.59 (s, 2H), 3.96 (s, 2H), 2.78 (s, 6H). MS (ES+): 259 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][CH2:7][C@@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[C:25]([O-:28])([O-])=O.[Cs+].[Cs+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34](C=O)[N:33]=1>CS(C)=O.CCOC(C)=O>[F:2][C:3]1[CH:20]=[C:19]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:18]=[CH:17][C:4]=1[CH2:5][O:6][CH2:7][C@@H:8]1[CH2:10][C@@H:9]1[CH:11]1[CH2:12][CH2:13][N:14]([C:34]2[N:35]=[CH:36][C:37]([CH:25]=[O:28])=[CH:32][N:33]=2)[CH2:15][CH2:16]1
Reactant: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1nccc(Cl)n1
Agent: Cl
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(COC[C@@H]2C[C@@H]2C2CCN(c3ncc(C=O)cn3)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.6 %

Procedure:
4-((1R,2R)-2-(((2-fluoro-4-(methylsulfonyl)benzyl)oxy)methyl)cyclopropyl)piperidine hydrochloride (Step D product) was dissolved in DMSO (7 ml) at RT under N2 and Cs2CO3 (539 mg, 1.654 mmol) was added. The mixture was stirred at RT for 5 min and chloropyrimidine aldehyde (113 mg, 0.794 mmol) in DMSO (1 mL) was added. The mixture was stirred at RT overnight. The mixture was diluted with EtOAc, washed with sat. NH4Cl, dried over MgSO4, evaporated to dryness. The crude material was purified by flash column (25 g SNAP, 25˜60% EtOAc in hexane) to afford 200 mg of the desired product (67.6%) as a white solid. LC/MS (m/z): 448 (M+H)+.
Reaction SMILES: C1C(=O)N([O:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[C:13](C3C4C=CC(O)=CC=4OC4C=3C=CC(C=4)=O)[CH:12]=2)=[O:10])C(=O)C1.C1C(=O)N(OC(C2C([C:52]3[C:62]4[CH:63]=[CH:64][C:65]([OH:67])=[CH:66][C:61]=4[O:60][C:59]4[C:53]=3[CH:54]=[CH:55][C:56]([CH:58]=4)=[O:57])=C(C(O)=O)C=CC=2)=O)C(=O)C1.[CH2:71]([OH:78])[C:72]([NH2:77])([CH2:75][OH:76])[CH2:73][OH:74].C(N(CC)CC)C>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH:15]1[C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]2[C:52]3([O:10][C:9](=[O:8])[C:11]=2[CH:16]=1)[C:53]1[CH:54]=[CH:55][C:56]([OH:57])=[CH:58][C:59]=1[O:60][C:63]1[CH:64]=[C:65]([OH:67])[CH:66]=[CH:61][C:62]3=1.[CH2:71]([C:72]([NH-:77])([CH2:75][OH:76])[CH2:73][OH:74])[OH:78]
Reactant: NC(CO)(CO)CO
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(C(=O)O)c(-c2c3ccc(=O)cc-3oc3cc(O)ccc23)c1
Reactant: O=C(O)c1cccc(C(=O)ON2C(=O)CCC2=O)c1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc2c(c1)C1(OC2=O)c2ccc(O)cc2Oc2cc(O)ccc21
Product: [NH-]C(CO)(CO)CO
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A 1000 ml round bottom flask was charged with 63.4 g (0.134 mole) of 5(6)-carboxyfluorescein N-hydroxysuccinimide ester, and 16.2 g (0.134 mole), of tris(hydroxymethyl)aminomethane, and 33.8 g (0.335 mole) of triethylamine. The contents of the flask were dissolved in 200 ml of dry dimethylformamide and stirred under nitrogen for 24 hours. A trace of 4-dimethylaminopyridine was added and the reaction was heated under nitrogen for another hour at 70° C. At the end of this period the reaction appeared complete by thin layer chromatography. The solvent was reduced down to a total volume of 200 ml of a dark red oily solution. This material was purified on preparatory HPLC apparatus using silica gel column and an elution solvent of acetic acid:2-propanol:ethyl acetate (2 8:70). The yield obtained was 20.5 g (32%). The desired structure was confirmed by 1H-NMR (CD3OD) which gave the following chemical shifts:
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:1]1([O:7][C:17]2[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=2[C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(OC2CCCCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of cyclohexanol (46.8 grams, 0.467 mol) in anhydrous THF (1 L) was added sodium hydride (20.3 grams, 0.508 mol) at −40° C. under nitrogen. The reaction mixture was allowed to warm slowly to room temperature and stir for another 1 hour. It was then cooled down to −55° C. and 2,6-dinitrobenzonitrile (78.4 g, 0.406 mol) was added. The reaction was stirred at room temperature overnight, then cooled down to −20° C., and citric acid (23.4 grams, 0.122 mol) was added. The mixture was then poured into ice water (5 L) which contained citric acid (7.8 g, 0.041 mol), stirred for 15 minutes, and the precipitated product was collected by filtration. The crude product was recrystallized from isopropanol (750 mL, heated to boiling, then cooled down to 0° C.), filtered, washed with isopropanol (300 mL), then air dried to give 84.4 g yellow solid. The solid was dissolved in dichloromethane (169 mL) and filtered through a plug of alumina to give the title compound as a pale yellow solid (83.2 g, 83.2%). 1H NR (400 MHz, DMSO-d6) δ 1.4 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 4.75 (m, 1H), 7.79 (dd, J=2.0, 8.0 Hz, 1H), 7.84-7.91 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1.C(O)(=O)C>C(OCC)(=O)C>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:1]1[CH:12]=[CH:16][CH:15]=[CH:14]1)#[N:5]
Reactant: N#Cc1ccccc1N
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-n1cccc1

Procedure:
A mixture of 2-aminobenzonitrile (0.01 mole), 2,5-dimethoxytetrahydrofuran (0.01 mole) and glacial acetic acid (10 ml) was heated under reflux for 30 minutes (TLC check). The acetic acid and ethyl acetate formed was evaporated off and the residue was purified using flash chromatography on silica gel (eluent: CH2Cl2). The pure fraction was recrystallized from the appropriate solvent (mostly ethanol).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]([NH2:11])=[C:5]2[C:9]([N:10]=1)=[N:8][CH:7]=[N:6]2.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:4]([NH2:11])[N:3]=1
Reactant: BrCC1CCOCC1
Reactant: Nc1[nH]c(Cl)nc2ncnc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Nc1nc(Cl)nc2c1ncn2CC1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a suspension of 2-chloro-1H-purin-6-amine (1.57 g) and potassium carbonate (2.57 g) in DMF (55 mL) was added 4-(bromomethyl)tetrahydro-2H-pyran (2.0 g) in one portion. The mixture was stirred at 90° C. overnight. The reaction mixture was taken up in chloroform/isopropanol (3:1, 100 mL) and was extracted with water (100 mL). The organics were separated and the aqueous was extracted with chloroform/isopropanol (3:1, 2×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give the title compound as an off-white solid (1.30 g, 52%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Yield: 73.3 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated under reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the resulting residue and the insoluble matter was filtered off whereas the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=98:2) to give 18.7 g of the titled compound (yield, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:19]([O:23][CH2:24][CH2:25]O)([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>O1CCCC1.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:25][CH2:24][O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(-c2ccc(O)cc2)c1C
Reactant: CC(C)(C)OCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnn(-c2ccc(OCCOC(C)(C)C)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.7 %

Procedure:
To a solution of 1-(4-Hydroxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (500 mg) in Reference Example 39 (2), 2-tert-butoxyethanol (480 mg) and triphenylphosphine (1.06 g) in tetrahydrofuran (20 ml) was added dropwise a solution of 40% azodicarboxylic acid diisopropylester in toluene (2.14 ml) under ice-cooling, and then stirred at room temperature overnight. After completion of the reaction, water was added thereto, extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 1-(4-tert-butoxyethoxyphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (870 mg) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:17])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28]Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:17][CH2:28][CH2:27][CH2:26][NH:25][C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCl
Reactant: CCOC(=O)c1cc2cc(Br)ccc2cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ccc2cc1OCCCNC(=O)OC(C)(C)C
Yield: 99.6 %

Procedure:
A mixture of 3.8 g (12.88 mmol) ethyl 7-bromo-3-hydroxynaphthalen-2-carboxylate, 3.0 g (15.5 mmol) 1-(tert.-butoxycarbonylamino)-3-chloropropane (prepared according to Helv. Chim. Acta 76 (1993), 1644), 2.0 g (14.5 mmol) potassium carbonate, and a catalytic amount of potassium iodide in 20 ml dry DMF was stirred at 90° C. for 6 h. It was poured into water, extracted three times with ethyl acetate, and the combined organic layers were washed three times with water, dried over sodium sulfate, and concentrated in vacuo. The intermediate was purified by chromatography on silica gel with toluene/acetone 9:1 to give 5.8 g (100%) of a yellow oil, which solidified rapidly upon standing.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Reactant: [OH-]
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extracted 2×with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08; H, 7.81; N, 5.86.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].Cl.[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2)=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH3:20][O:21][C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:27]2)=[O:23]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: COC(=O)c1ccc2c(c1)CNC2
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(C(=O)OC)cc4C3)cc21
Yield: 50.1 %

Procedure:
128 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 109 mg of 5-methoxycarbonylisoindoline hydrochloride, 228 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 104 mg of the target compound.
Reaction SMILES: [CH3:1][Li].Cl[C:4]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=3[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10][CH2:9][C:8]=2[N:7]=[C:6]([CH3:26])[N:5]=1>CCOCC.O.S>[Cl:19][C:17]1[CH:16]=[CH:15][C:13]2[C:14]3[C:4]([CH3:1])=[N:5][C:6]([CH3:26])=[N:7][C:8]=3[CH2:9][N:10]=[C:11]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:12]=2[CH:18]=1
Reactant: [Li]C
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Agent: S
Solvent: O
Solvent: CCOCC
Product: Cc1nc(C)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dropwise 13.2 ml (18.5 mmol) of a 1.4 M ether solution of methyl lithium was added to a suspension of 1.7 g (8.9 mmol) of cuprous iodide in 50 mL of ether which was cooled to 0°. A solution of 0.8 g (2.2 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine in 30 mL of ether was added dropwise to the ether solution of lithium dimethylcuprate which was further cooled to -25°. The mixture was stirred at -25° for 1 hr, warmed to room temperature, diluted with water and saturated with hydrogen sulfide. The resulting precipitate was removed by filtration over celite and he filtrate was concentrated at reduced pressure. Purification of the residue by column chromatography (silica gel, 10 g; eluent, 20% ether in methylene chloride) gave an oil which was crystallized from a mixture of ether and petroleum ether to give off-white needles, mp 121°-124°.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([N+:11]#[C-:12])([CH3:10])([CH3:9])[CH3:8].[CH3:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>Cl(O)(=O)(=O)=O>[C:7]([NH:11][C:12]1[N:6]2[C:2]([S:3][CH:4]=[CH:5]2)=[N:1][C:13]=1[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH3:16])([CH3:10])([CH3:9])[CH3:8]
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nccs1
Reactant: Cc1ccccc1C=O
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1ccccc1-c1nc2sccn2c1NC(C)(C)C

Procedure:
Compound 35 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-amino thiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-methylbenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
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.[CH3:14][CH:15]1[NH:24][CH2:23][CH2:22][C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]1=2>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:24]3[CH2:23][CH2:22][C:21]4[N:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2ncccc21
Product: CC1c2cccnc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

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-methyl-5,6,7,8-tetrahydro-[1,6]naphthyridine to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:21]=1[CH:22]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:21]=1/[CH:22]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1cc(C(F)(F)F)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1Cl)C2=O
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a solution of 6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 13 (0.120 mg, 0.485 mmol) in toluene (10 mL) was added 2-chloro-5-(trifluoromethyl)benzaldehyde 75 (0.101 mg, 0.485 mmol). PTSA (0.184 mg, 0.971 mmol) was added to the reaction mass, reaction stirred at 100° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 157 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 15% ethyl acetate in hexane to afford yellow coloured solid (E)-2-(2-chloro-5-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2, 3-dihydro-1H-inden-1-one 157.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9].[OH-].[Na+]>CO>[CH3:7][S:8]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:10])=[O:9]
Reactant: NCCC(=O)O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)NCCC(=O)O
Reaction time: 3 h

Procedure:
22.3 g of β-alanine are dissolved in 125 ml of 2N MeOH. 20 ml of methanesulfonyl chloride and 145 ml of 2N NaOH are simultaneously added dropwise at 0°-5° C., with vibromixing, and the mixture is vibrated at room temperature for 3 hours. The solution is extracted with ether and the extract is diluted to 400 ml and stirred with a strongly acid ion exchanger (Lewatit® S 100) until the pH reaches about 2. The solution is then evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, the mixture is dried over sodium sulfate and DCA is added until an alkaline reaction is obtained. The precipitate which separates out is filtered off, washed with ethyl acetate and ether, dried and recrystallized from tetrahydrofuran.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[I-].[F:14][C:15]([F:20])([F:19])[CH2:16][CH2:17][Zn+]>CN(C=O)C.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>[CH3:12][C:11]1[C:2]([CH2:17][CH2:16][C:15]([F:20])([F:19])[F:14])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: FC(F)(F)CC[Zn+]
Reactant: COC(=O)c1cnc(Cl)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(CCC(F)(F)F)c(C)c1
Temperature: 55 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
To a suspension of zinc powder (2.49 g, 38.1 mmol) in THF (15 mL), 1,2-dibromoethane (0.21 g, 1.1 mmol) and trimethylsilyl chloride (0.12 g, 1.1 mmol) are added. After stirring at rt for 20 minutes, 1,1,1-trifluoro-3-iodopropane (6.10 g, 27.2 mmol) is added, and the mixture is stirred at 55° C. for 1 hour to give a solution of (3,3,3-trifluoropropyl)zinc iodide in THF. To a mixture of methyl 6-chloro-5-methylnicotinate (2.02 g, 10.9 mmol, Step-1) and tetrakis(triphenylphosphine)palladium(0) (1.01 g, 0.87 mmol) in DMF (15 mL) is added the zinc reagent, and the mixture is stirred at 55° C. for 12 hours. After cooling to rt, the mixture is poured onto water (100 mL), and the aqueous layer is extracted with EtOAc (30 mL×2). The combined organic layer is dried over sodium sulfate, and after filtration, the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica-gel eluting with n-hexane/EtOAc (5:1 to EtOAc only) to give 2.32 g (86% yield) of the title compound as an orange solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].[C:17]1([CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Li].IC1C=CC=CC=1C>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:24])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: [Li]c1ccccc1C
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Agent: Cc1ccccc1I
Product: CCSc1ncc(C(=O)c2ccccc2C)c(N)n1

Procedure:
The same procedure was used as described in Example 2, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (from Example 1) and a solution of 2-tolyllithium (˜3 equiv, freshly prepared from 2-iodotoluene, as in Example 2A), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-o-tolyl-methanone as a white solid. MS (M+H)+: 274.