Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7](Cl)=[O:8].[CH3:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[CH3:10][CH:11]1[CH2:16][CH2:15][N:14]([C:7]([C:3]2[CH:4]=[N:5][O:6][C:2]=2[CH3:1])=[O:8])[CH2:13][CH2:12]1
Reactant: Cc1oncc1C(=O)Cl
Reactant: CC1CCNCC1
Product: Cc1oncc1C(=O)N1CCC(C)CC1

Procedure:
of melting point 44° to 45° C., prepared from 5-methyl-4-isoxazolecarboxylic acid chloride and 4-methyl-piperidine.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])(C)(C)C.C([O:22][B:23](OCCCC)[O:24]CCCC)CCC.Cl>O1CCCC1>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([B:23]([OH:24])[OH:22])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CCCCOB(OCCCC)OCCCC
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OB(O)c1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.8 %

Procedure:
To a suspension of sodium hydride (122 mg, 5.1 mmol) in anhydrous tetrahydrofuran (20 mL) was added 5-bromoindole (1.0 g, 5.1 mmol) (Aldrich) at 0° C. After 15 min. of stirring at 0° C., the reaction was cooled to −78° C., and tert-butyllithium (10.2 mmol, 1.7M in hexane) (Aldrich) was added dropwise (a white precipitate immediately formed). After 10 min. tri-n-butylborate (2.75 mL, 10.2 mmol) was added dropwise. The reaction was allowed to slowly warm to room temperature, then the suspension was poured into an ice cold solution of 1N HCl. The organic phase was separated, and the aqueous phase was washed with ether. The combined organic extracts were extracted with 1N NaOH (3×25 mL), and the combined alkaline extracts were acidified to pH 1 with 1N HCl. The product was then extracted with ether, and the combined ether layers were dried over magnesium sulfate and concentrated in vacuo to yield a brownish solid. The product was recrystallized from boiling water to yield 450 mg (55%) white crystals (mp >290° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([CH:14]=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=CN1CCN(c2ccc(Br)cn2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=CN1CCN(c2ccc(-c3ccc(F)cc3)cn2)CC1
Yield: 94.7 %

Procedure:
4-(5-Bromo-pyridine-2-yl)-piperazine-1-carbaldehyde (100 mg, 0.37 mmol), 4-Fluorobenzeneboronic acid (55 mg, 0.39 mmol), (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (10 mg, 0.01 mmol), Toluene (2 ml), EtOH (0.5 ml) and 2M Na2CO3 solution (0.5 ml, 1 mmol) were heated at 80° C. under N2 overnight. After cooling the mixture was diluted with toluene and separated. The organic phase was washed with water and brine, filtered through a pad of celite and dried over Na2SO4. The solvent were removed in vacuo affording 100 mg (94%) of the title product as a beige powder.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19].[C:20]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[OH:18][C@@H:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C@H:12]1[NH:11][C:8]1[S:9][C:10]2[C:2]([CH3:20])=[C:3]([OH:19])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(O)ccc2nc(N[C@@H]3CCCC[C@H]3O)sc12
Temperature: 120 °C
Yield: 17 %

Procedure:
To the solution of 7-bromo-2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (117 mg, 0.34 mmol, 1.0 eq) in 1 mL DMF in a microwave vial was added trimethylboraxine (128 mg, 1.02 mmol, 3.0 eq), Pd(Cl2)dPPf (27 mg, 0.034 mmol, 0.1 eq) and 1 mL of 2M Na2CO3 solution at room temperature. Thereafter, the reaction mixture was heated in the microwave at 120° C. for 15 minutes. The reaction was quenched with saturated NaHCO3 solution (25 ml) and the aqueous phase extracted with ethyl acetate (50 mL×3), combined organic layers dried over Na2SO4, filtered and condensed under reduced pressure. Purification over ISCO using a gradient of 0%-18% methanol-DCM gave 17 mg of product as brownish powder in 17% yield. LC/MS (m/z) [279.1] (MH+)
Reaction SMILES: N1C=CC=CC=1.CN(C)C=O.S(Cl)([Cl:14])=O.O[CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[Cl:14][CH2:17][C:18]1[CH2:19][S:20][C@@H:21]2[C@H:41]([NH:42][C:43](=[O:51])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:40](=[O:52])[N:22]2[C:23]=1[C:24]([O:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]
Reactant: O=S(Cl)Cl
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reaction time: 0.17 h

Procedure:
24 ml (0.3 mole) of pyridine, 400 μl of dimethylformamide and 21.6 ml (0.3 mole) of thionyl chloride are added to a solution of 103 g (0.2 mole) of benzhydryl 3-hydroxymethyl-7β-phenylacetamido-3-cephem-4-carboxylate (prepared, for example, in accordance with Helv. Chim. Acta 57, 2044 (1974)) in 3.5 l of absolute tetrahydrofuran, while cooling with ice. After 10 minutes, the mixture is concentrated on a rotary evaporator, the residue is taken up in 2 l of ethyl acetate and the mixture is extracted by shaking twice with sodium bicarbonate solution and once with water. The organic phase is extracted by stirring with 50 g each of kieselguhr and active charcoal and the extract is filtered with suction over a frit covered with silica gel. The filtrate is then dried over magnesium sulphate and concentrated, the residue is taken up in 200 ml of methylene chloride and the product is precipitated with petroleum ether.
Reaction SMILES: C(NC(C1OC2(CCN([C:18](=[O:30])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=3)CC2)CN(CC2C=CC=CC=2)C1)=O)C(C)=O>C1COCC1>[CH:26]([O:25][C:22]1[CH:23]=[CH:24][C:19]([CH:18]=[O:30])=[CH:20][C:21]=1[CH3:29])([CH3:28])[CH3:27]
Reactant: CC(=O)CNC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccc1OC(C)C
Temperature: 75 °C
Yield: 164 %

Procedure:
To N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (136 mg, 0.26 mmol) in THF (3 mL) was added Burgess' Salt (155 mg, 0.65 mmol) and the reaction mixture was heated at 75° C. in a sealed vial for 2 hours. The solvents were removed under reduced pressure, and the residue was dissolved in DMF (1 mL), filtered and purified by Waters preparative LC/MS (1-99% ACN/H2O (5 mM HCl)). The desired fractions were concentrated in vacuo and the residue partitioned between EtOAc/saturated aqueous NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to yield 8-benzyl-10-(5-methyloxazol-2-yl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (76 mg, 58%) as a foam. ESI-MS m/z calc. 503.6. found 504.5 (M+1)+; Retention time: 1.74 minutes (3 min run).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:20][CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:43](SCC(COC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)O)CCCCCCCCCCCCCCC.CCI>>[CH2:1]([S:17][CH2:18][CH:19]([CH2:22][O:23][C:24]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[O:20][CH2:21][CH3:43])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Reactant: CCCCCCCCCCCCCCCCSCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCI
Product: CCCCCCCCCCCCCCCCSCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC

Procedure:
This compound was prepared in an analogous manner to that of (±)-1-S-hexadecyl-2-O-methyl-3-O-tritylthioglycerol from 10.0 grams (0.02 mole) of (±)-1-S-hexadecyl-3-O-tritylthioglycerol and 3.3 grams (0.03 mole) of CH3CH2I to provide 10.0 grams of crude product as an oil. 1H-NMR (CDCl3): delta, 0.7-1.7[m, 34H, (CH2)14CH3, CH3 --CH2 --O], 2.3-2.8(m, 4H, CH2 --S--CH2), 3.5-3.9[m, 5H, OCH2 --CH3, CHCH2O], 7.1-7.5 [m, 15H, C(C6H5)3 ].
Reaction SMILES: Cl[C:2]1[CH:7]=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[CH2:54][O:53][CH2:52][C@H:51]2[OH:55])=[N:45][C:46]=1[CH2:47][CH3:48].ICCC>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:56][CH3:57])[C:44]([NH:49][C@H:50]2[C@@H:51]([O:55][CH2:3][CH2:2][CH3:7])[CH2:52][O:53][CH2:54]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@H]1COC[C@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Solvent: CCCI
Product: CCCO[C@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}tetrahydrofuran-3-ol and 1-iodopropane and making non-critical variations provided the title compound as a light yellow oil. IR (liq.) 2967, 2936, 2875, 1606, 1566, 1483, 1441, 1396, 1287, 1230, 1203, 1124, 1078, 1058, 1046 cm−1; OAMS supporting ions at: ESI+ 420.2; MS (EI) m/z 419 (M+); HRMS (FAB) calcd for C22H30CLN3O3+H1 420.2054, found 420.2052. Anal. Calcd for C22H30ClN3O3: C, 62.92; H, 7.20; N, 10.01. Found: C, 62.78; H, 7.28; N, 10.01.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][NH2:25]>>[OH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:26])[NH:24][N:25]=[C:9]1[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: NNC(=O)Nc1ccccc1O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)Nc1ccccc1O

Procedure:
ninhydrin, 4-(2-hydroxyphenyl)-semicarbazide hydrochloride
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:12]([OH:14])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:14]
Reactant: O=C(O)c1cnc2ccccc2c1O
Reactant: Nc1ccccc1
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: CN(C)C=O
Product: O=C(Nc1ccccc1)c1c[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 μL, 0.2 mmol) in DMF (1 mL) was added aniline (18.2 μL, 0.2 mmol) and the reaction mixture was stirred at room temperature for 3 h. The resulting solution was filtered and purified by HPLC (10-99% CH3CN/H2O) to yield 4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45%). 1H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J=8.1, 1.1 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H); HPLC ret. time 3.02 min, 10-99% CH3CN, 5 min run; ESI-MS 265.1 m/z (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.[CH:10]1([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([NH:16][C:17]([CH:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]3[N:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=3)[CH2:23][CH2:24]2)=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(NC1CCCCC1)C1CCNCC1
Reactant: Nc1ccnc(CCl)n1
Product: Nc1ccnc(CN2CCC(C(=O)NC3CCCCC3)CC2)n1

Procedure:
The title compound is prepared according to the reactions described above starting from 2-chloromethyl-pyrimidin-4-ylamine and piperidine-4-carboxylic acid cyclohexylamide; LC-MS A: tR=0.47 min; [M+H]+=318.12.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:10])[O:9][C@@H:5]2[C@@H:4]([O:12][CH2:13][C:14](OCC)=[O:15])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[NH2:1][C@H:2]1[C@@H:6]2[O:7][C:8]([CH3:10])([CH3:11])[O:9][C@@H:5]2[C@@H:4]([O:12][CH2:13][CH2:14][OH:15])[CH2:3]1
Reactant: CCOC(=O)CO[C@H]1C[C@@H](N)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](OCCO)C[C@H]2N
Yield: 65.3 %

Procedure:
A solution of ethyl 2-((3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)acetate (4.2 g, 16.2 mmol, 1.00 equiv.) in dry tetrahydrofuran (50 mL) was slowly added to a suspension of lithium aluminum hydride (1.23 g, 32.4 mmol, 2.00 equiv.) in tetrahydrofuran (50 mL). The mixture was heated at reflux for about 1 hour, and then water was added (2 mL). After the solids were collected by filtratration, the solids were washed with tetrahydrofuran (50 mL) and then dried in vacuo to give the title product as a yellow oil (2.3 g, 65%). MS: m/z=218 (MH)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23]Cl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4].[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[CH2:27]([N:30]([CH2:31][CH2:32][CH3:33])[CH2:2][C:3]([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21][C:22](=[O:25])[CH2:23][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:4])[CH2:28][CH3:29]
Reactant: CCCNCCC
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)Nc1cccc2c1C(=O)c1c(NC(=O)CN(CCC)CCC)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Add 0.4 g, 1.0 mmol 1,8-bis(chloroacetamido)anthraquinone (compound 3) with 0.5 ml TEA, and 0.7 ml, 6 mmole Dipropylamine, dissolved in 20 ml dehydrated dimethylformamide (DMF). The mixture is reacted in a mini-reactor. The reaction temperature is 120° C. in the oil bath and the reaction time is 30 minutes. The reacted mixture is poured into 50 ml ice water and is filtered to collect precipitate. The precipitate is recrystallized from ethanol to get yellow compound 3n.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]([O:24]C)=O)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:9]=2)=[CH:4][CH:3]=1.O.[NH2:46][NH2:47]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]([NH:46][NH2:47])=[O:24])=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cnc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cn12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cn12

Procedure:
A mixture of 740 mg methyl 6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]imidazo[1,2-a]pyridine-3-carboxylate (compound in Production Example 273), 0.32 mL hydrazine monohydrate and 20 mL ethanol was heated for 6 hours under reflux. The reaction solution was evaporated, and the resulting residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 283 mg of the title compound as a color amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=2)[NH:14][CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC#N>O.C(Cl)Cl.CN(C=O)C>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:11][CH2:10][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COc1ccc2[nH]cc(CCBr)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCn3cc([N+](=O)[O-])cn3)c2c1

Procedure:
A microwave vial was charged with 4-nitro-1H-pyrazole (1.0 g, 8.84 mmol), 3-(2-bromoethyl)-5-methoxy-1H-indole (2.25 g, 8.84 mmol), Cs2CO3 (5.76 g, 17.69 mmol), MeCN (75.0 mL) and DMF (5.0 mL). The tube was sealed and the reaction mixture was irradiated in the microwave to 100° C. for 10 min with cooling. The reaction mixture was diluted with water and DCM, then the org. layer was separated and the aq. layer was extracted with DCM. The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification was performed by FC (EtOAc/hex 1:4) to yield 5-methoxy-3-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)-1H-indole as a yellow solid, which was used in the next step without further purification. LC-MS conditions B: tR=0.70 min, [M+H]+=287.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:19]=[C:20]([C:22]3([C:25]([OH:27])=[O:26])[CH2:24][CH2:23]3)[N:21]=2)[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[C:14](=[O:18])[O:13][CH2:12]3)=[CH:7][CH:8]=1.[CH3:28][C@@H:29](O)[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:28][C@@H:29]([O:26][C:25]([C:22]1([C:20]2[N:21]=[C:4]3[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[C:6]([C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[C:14](=[O:18])[O:13][CH2:12]5)[N:5]3[N:19]=2)[CH2:23][CH2:24]1)=[O:27])[CH2:30][CH3:31]
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)n2nc(C3(C(=O)O)CC3)nc12
Reactant: CC[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](C)OC(=O)C1(c2nc3c(OC)ccc(-c4ccc5c(c4)COC5=O)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A mixture of 1-[8-methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylic acid (400 mg, 1.095 mmol), (2R)-butan-2-ol (122 mg, 1.64 mmol), DMAP (147 mg, 1.20 mmol) and EDCI.HCl (231 mg, 1.20 mmol) in DCM (10 mL) was stirred at RT overnight before it was evaporated to dryness. Column chromatography (gradient MeOH 0 to 5% in DCM) followed by recrystallization in EtOH and freeze drying afforded the title compound as colorless powder (138 mg, 30%). HPLC-Retention time (XE Metode 7 CM): 2.33 minutes. Detected “M+1”-mass: 422.15. Calculated “M+1”-mass: 422.17. 1H NMR (DMSO, 400 MHz): δ=8.23 (br s, 1H), 8.14 (dd, 1H, J=8.0, 1.6 Hz), 7.99 (d, 1H, J=8.0 Hz), 7.41 (d, 1H, J=8.2 Hz), 7.24 (d, 1H, J=8.2 Hz), 5.51 (s, 2H), 4.78 (h, 1H, J=6.3 Hz), 4.04 (s, 3H), 1.62-1.38 (m, 6H), 1.13 (d, 3H, J=6.3 Hz), 0.78 (t, 3H, J=7.4 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.CC(C)=[O:20]>>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([OH:20])=[O:10])=[CH:7][CH:6]=1
Reactant: O=Cc1ccc(Oc2c(F)cccc2F)cc1
Reactant: CC(C)=O
Product: O=C(O)c1ccc(Oc2c(F)cccc2F)cc1
Yield: 70 %

Procedure:
To a cold solution of 4-(2,6-difluoro-phenoxy)-benzaldehyde (1 g, 4.2 mmol) in acetone (10 mL) was added the Jone's reagent slowly drop wise at 0° C. until the reaction completes. The acetone was removed completely and the residue was diluted with water, extracted with ethyl acetate and the combined organic layers were washed with water and brine, then dried over sodium sulphate and concentrated to obtain the title compound (0.75 g, 70%)
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH2:12])[S:10][CH:11]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:8]=[C:9]([NH:12][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[S:10][CH:11]=1
Reactant: Nc1nc(-c2sccc2Cl)cs1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3sccc3Cl)cs2)cc1

Procedure:
The title compound was prepared from 4-(3-chloro-2-thienyl)-1,3-thiazol-2-amine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a brown-red solid (5.3 mg) with purity >90%. MS (pos) m/z 399.2, 401.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-methyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[N:6]([CH3:9])=[C:7]=[S:8]>CO>[C:1]([NH:4][NH:5][C:7](=[S:8])[NH:6][CH3:9])(=[O:3])[CH3:2]
Reactant: CN=C=S
Reactant: CC(=O)NN
Solvent: CO
Product: CNC(=S)NNC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred solution of acetohydrazide (3.7 g, 50 mmol) in methanol (30 mL) was added a solution of compound isothiocyanatomethane (3.65 g, 50 mmol) in methanol (50 mL) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to give crude product (7 g) as a white solid which was used in the next step without further purification. LC-MS (ESI) m/z: 148 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([Mg]Br)[CH:11]=[CH2:12].C1COCC1>>[CH3:12][C:11](=[CH2:10])[CH:5]([C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=1)[OH:6]
Reactant: Cc1cccc(C=O)c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=C(C)C(O)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 51 %

Procedure:
3-Methylbenzaldehyde (Aldrich 97%, 62 g, 0.5 mol) was added drop-wise over 1 hour to a commercial solution of 2-propenyl magnesium bromide in THF (Aldrich 0.5 N, 800 ml, 0.4 mol), at −78° C. under nitrogen. The cooling bath was removed and the reaction stirred for 5 hours, before being cooled to 0° C. A saturated aqueous solution of ammonium chloride (300 ml) was added drop-wise at such a rate that the temperature was kept below 20° C. Diethyl ether (600 ml) was then added and the reaction was transferred to a separating funnel. After shaking vigorously, the phases were separated. The organic phase was washed with water and saturated aqueous sodium bicarbonate. Each aqueous phase was re-extracted with diethyl ether. The organic fractions were combined and dried over solid anhydrous sodium sulfate. The solid was filtered off, rinsed with diethyl ether and the solvents were removed under vacuum. The product was purified by column chromatography on silica gel (eluent: heptanes/ethyl acetate 5:1) followed by distillation through a 20-cm Widmer column. 33 g of the desired product were obtained (yield=51%). B.P.=55° C./0.009 mbar