Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[C:16]([F:19])([F:18])[F:17])[CH:7]=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>CCCCCC.CCOCC>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:28]([C:25]3[CH:24]=[CH:23][C:22]([S:21][CH3:20])=[CH:27][CH:26]=3)(=[O:29])=[O:30])=[CH:11][C:10]=2[C:16]([F:17])([F:19])[F:18])[CH:7]=1
Reactant: Nc1ccc(Oc2cncc(Cl)c2)c(C(F)(F)F)c1
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CSc1ccc(S(=O)(=O)Nc2ccc(Oc3cncc(Cl)c3)c(C(F)(F)F)c2)cc1
Yield: 33.9 %

Procedure:
Using the method of Example 17.4, 2-(3-chloro-5-pyridyloxy)-5-aminobenzotrifluoride (0.394 g) and 4-methylthiobenzenesulfonyl chloride (0.34 g ) [H. Burton, et al. J. Chem. Soc. 1948, 604-605] were combined to provide, after flash chromatography and trituration with hexane/ether, the title compound as crystals (0.22 g). mp 109.5-111° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14](O)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]2[C:13]3[C:7]([CH2:8][CH:9]([C:14]([NH:31][CH:28]4[CH2:30][CH2:29]4)=[O:15])[S:10][C:11]=3[N:12]=1)=[N:6][N:5]2[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1
Reactant: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)O)C3)c1C
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(C)cnc(Cn2nc3c4c(nc(N)nc42)SC(C(=O)NC2CC2)C3)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture composed of 4-amino-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-7,8-dihydro-2H-6-thia-1,2,3,5-tetraazaacenaphthylene-7-carboxylic acid of Example 8 (80 mg), cyclopropylamine (0.029 mL), 1-hydroxybenzotriazole monohydrate (32 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg) and dehydrated N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and sequentially washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (dichloromethane-methanol) to obtain the title compound (30 mg, 34%) as a solid.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: CN1CCCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Product: CN1CCCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with 1-methyl-1,4-diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinamide.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1.C(O)(=O)C.C[N:37]1[CH:41]=[CH:40][N:39]=[C:38]1[CH:42]=O.C([BH3-])#N.[Na+]>CO>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:16]=[C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH3:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]=2[CH:31]=1)[CH2:42][C:38]1[NH:37][CH:41]=[CH:40][N:39]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(CNCc3ncc[nH]3)cc2n1CCC
Reactant: Cn1ccnc1C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCc1nc2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2n1CCC
Temperature: 0 °C
Reaction time: 48 h

Procedure:
The compound (64.0 mg) obtained in Example 126-1 was dissolved in methanol (1.3 ml) and added with acetic acid (0.065 ml) and 1-methyl-2-imidazole carboxaldehyde (16.6 mg), followed by cooling to 0° C. Then, the solution was added with sodium cyanoborohydride (14.2 mg) and stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform. After washing with a 1 mol/l sodium hydroxide aqueous solution, the solution was subjected to extraction with chloroform. The organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (30.0 mg) of the subject compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])[S:5][C:6]=1[CH3:7].CC(C)([O-])C.[K+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[C:4](=[N:8][C:9]([C:11]23[CH2:20][CH:15]4[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]4)[CH2:12]2)[CH2:18]3)=[O:10])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(NC(=O)C23CC4CC(CC(C4)C2)C3)sc1C
Reactant: ClCc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1sc(=NC(=O)C23CC4CC(CC(C4)C2)C3)n(Cc2ccncc2)c1C
Temperature: 250 °C
Yield: 36.7 %

Procedure:
To a solution of Example 97A (145 mg, 0.50 mmol) in DMF (5 mL) was added potassium tert-butoxide (120 mg, 1.10 mmol) and the hydrochloride salt of 4-chloromethyl-pyridine (82 mg, 0.5 mmol). The mixture was heated in a SmithSynthesizer™ microwave at 250° C. for 15 minutes. The mixture was diluted with ethyl acetate, washed with 1M NaHCO3, and layers were separated. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The residue was recrystallized from ethyl acetate to afford the title compound (70 mg, 36%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54-1.72 (m, 6 H), 1.75 (d, J=2.4 Hz, 6 H), 1.91 (s, 3 H), 2.09 (d, J=0.7 Hz, 3 H), 2.17 (d, J=0.7 Hz, 3 H), 5.44 (s, 2 H), 7.06-7.20 (m, 2 H), 8.50-8.56 (m, J=6.1 Hz, 2 H); MS (ESI+) m/z 382 (M+H)+; Anal. Calculated for C22H27N3OS.0.2H2O: C, 68.61; H, 7.17; N, 10.91. Found: C, 68.56; H, 7.12; N, 10.76.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:20][C:21]([NH2:23])=[NH:22])=[N:4][CH:3]=1.Cl.NC(N)=N.O>CS(C)=O>[C:6]([O:18][C:17](=[O:19])[CH2:16][CH2:15][NH:14][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[NH:20][C:21]([NH2:23])=[NH:22])=[CH:10][CH:9]=1)=[O:13])([CH3:11])([CH3:7])[CH3:5]
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(C(=O)NCCC(=O)O)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCNC(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 80 °C
Yield: 33.7 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine ##STR61## NaH (114 mg, 60% dispersion in mineral oil, 2.85 mmol) was added portionwise to a stirred solution of guanidine hydrochloride (272 mg, 2.85 mmol) in DMSO (8 mL) and the solution was heated at 80° C. for 20 min. N-[(1,4-Dichloro-7-isoquinolinyl)carbonyl]-P-alanine t-butyl ester (420 mg, 1.14 mmol) was added and the mixture heated at 90° C. overnight. The cooled mixture was poured into water, extracted with EtOAc, and the combined organic extracts were washed with water, saturated brine, dried (Na2SO4) and evaporated in vacuo. The residue was crystallised from i-Pr2O-CH2Cl2 to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)carbonyl]-β-alanine t-butyl ester (190 mg, 0.48 mmol).
Reaction SMILES: [N+:1]([C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].[OH-].[Na+].CCOC(C)=O>CCO>[N+:1]([C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1cccc(C(F)(F)F)c1[N+](=O)[O-]
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 93.3 %

Procedure:
N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p. 107) (3.6 g) was dissolved in EtOH and heated to 105° C. prior to the addition of 1N NaOH (60 ml) and 50% NaOH (10 ml). After 2.5 h, the reaction was cooled to rt and EtOAc was added. The organic layer was washed with water and brine. Then it was dried and concentrated to give a crude 2-nitro-3-trifluoromethyl-phenylamine (2.79 g): 1H NMR (CDCl3, δppm, 300 mHz) 5.0 (s, 2H), 7.02 (d, 1H), 7.10 (d, 1H), 7.38 (t, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]([OH:18])[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[C:51]1[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=1>C1COCC1.O>[CH3:1][C:2]1[C:3]([CH:16]([O:18][C:51]2[CH:58]=[CH:57][C:54]([CH:55]=[O:56])=[CH:53][CH:52]=2)[CH3:17])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(C)O)C(C)(C)CCC2(C)C
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(C)Oc1ccc(C=O)cc1)C(C)(C)CCC2(C)C

Procedure:
A solution of 1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanol (246 mg; 1.0 mmol), triphenylphosphine (262 mg; 1.0 mmol), diethyl azodicarboxylate (0.153 ml; 1.0 mmol) and 4-hydroxybenzaldehyde (183 mg; 1.5 mmol) in THF (20 ml) was stirred at 0° C. for 1.5 hours and for 16 hours at room temperature. Water was added (20 ml) and the mixture was extracted with methylene chloride (3×25 ml). The combined organic phases were dried and evaporated. The residue was purified on column chromatography using ethyl acetate: hexane (1:3) as eluent. Yield 180 mg.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(N(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[N:60]1([CH:66]2[CH2:71][CH2:70][CH:69]([C:72]3[CH:77]=[CH:76][C:75]([NH2:78])=[CH:74][CH:73]=3)[CH2:68][CH2:67]2)[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:78][C:75]4[CH:76]=[CH:77][C:72]([CH:69]5[CH2:68][CH2:67][CH:66]([N:60]6[CH2:61][CH2:62][O:63][CH2:64][CH2:65]6)[CH2:71][CH2:70]5)=[CH:73][CH:74]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(C2CCC(N3CCOCC3)CC2)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Agent: O=S(=O)(N(c1ccccc1)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4ccc(C5CCC(N6CCOCC6)CC5)cc4)nn23)c1

Procedure:
The title compound was prepared in the following manner: N-tert-Butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide (70 mg, 0.2 mmol), N-Phenylbis(trifluoromethanesulphonimide) (82.6 mg, 0.231 mmol), N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol), and N,N-Dimethylformamide (2 mL, 20 mmol) and stir at room temperature for half an hour. Added 4-(4-Morpholin-4-yl-cyclohexyl)-phenylamine (280 mg, 1.1 mmol) and stir at 80° C. overnight. The mixture was concentrated and purified using the gilson. The most pure fractions were combined basified with sat. sodium bicarbonate and extracted with DCM, dried filtered and concentrated to give a yellow solid (30 mg, 20%). MP 160-163 C. LCMS (E/I+) 589 (M+H). NMR 1H (DMSO-d6)-9.44 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 8.33-8.40 (m, 1H), 7.86 (d, 1H, J=8.03), 7.59-7.76 (m, 3H), 7.18-7.24 (m, 2H), 6.98 (d, 1H, J=4.8 Hz), 3.60-3.64 (m, 2H), 3.55-3.59 (m, 1H), 2.55-2.64 (m, 1H), 2.49-2.51 (m, 4H), 2.36-2.42 (m, 2H), 2.14-2.19 (m, 1H), 1.89-1.98 (m, 2H), 1.78-1.88 (m, 2H), 1.44-1.54 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[NH:28][CH2:27]1>>[CH3:25][C@@H:26]1[O:30][C:29](=[O:31])[N:28]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[CH2:27]1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)OC4=O)cc3)CC2)nc1C
Yield: 75.5 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (435 mg) described in Preparation Example 176 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (308 mg) was obtained.
Reaction SMILES: CN(C=O)C.[C:6](Cl)(=O)[C:7]([Cl:9])=[O:8].[CH3:12][O:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][C:22](CC(O)=O)=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[C:25]2[C:20](=[CH:21][C:22]([CH2:6][C:7]([Cl:9])=[O:8])=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1cccc2cc(CC(=O)O)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2cc(CC(=O)Cl)ccc12
Temperature: 0 °C

Procedure:
140 μl (1.8 mMol) DMF are added to an ice-cooled solution of 3.6 ml (43 mMol) oxalylchloride in 150 CH2Cl2. Then a suspension of 8.8 g (36 mMol) 6-carboxymethyl-naphthalene-1-carboxylic acid methyl ester in 400 ml CH2Cl2 is added during 1 h. After 1.5 h stirring in the ice-bath, the reaction mixture is concentrated in vacuo, yielding the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:22][CH3:23])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]3[CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:21]=1.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(O)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C>[CH3:23][O:22][C:9]1[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:34][CH2:35][N:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[C:15](=[O:17])[O:16][C:11]=2[CH:10]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCCBr)CCC3
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCCN1CCN(c2ccccc2)CC1)CCC3
Yield: 97 %

Procedure:
Method B (10 h at 80° C.); starting materials: 8-(5-bromopentyloxy)-2,3-dihydro-7-methoxycyclopenta[c][1]benzopyran-4(1H)-one (example 85) and 1-phenylpiperazine; yield 97%; fusion point 118°-120° C. (from isopropanol). Fumarate (x 0.5 C4H4O4): method E; yield 93%; fusion point 153°-155° C. (from isopropanol and TBME).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([OH:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[N:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>>[N:12]1([C:18]([O:11][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[N:8]([C:18]([N:12]3[CH2:17][CH2:16][S:15][CH2:14][CH2:13]3)=[O:19])[N:7]=2)=[O:19])[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)N1CCSCC1
Reactant: Oc1n[nH]c2cc(F)ccc12
Product: O=C(Oc1nn(C(=O)N2CCSCC2)c2cc(F)ccc12)N1CCSCC1

Procedure:
In analogy to example 1, 200 mg (1.315 mmol) of 6-fluoro-1H-indazol-3-ol were reacted with 261.4 mg (1.578 mmol) of thiomorpholine-4-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([C:17]3[N:18]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][C:21]=3[CH3:22])=[O:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCCC1.C1([Mg]Br)C=CC=CC=1.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][C:15]([C:17]3[N:18]=[C:19]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][C:21]=3[CH3:22])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[OH:16])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(-c2cccnc2)nc1C(=O)CN1CCN(c2ccc(F)cc2)CC1
Agent: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1[nH]c(-c2cccnc2)nc1C(O)(CN1CCN(c2ccc(F)cc2)CC1)c1ccccc1
Yield: 82.9 %

Procedure:
A mixture of 1.5 g of 2-[4-(4-fluorophenyl)-1-piperazinyl]-1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone in 20 ml of dry tetrahydrofuran and 10 ml of 1.7M phenyl magnesium bromide in 10 ml of ether was reacted as described in Example 41 giving 2 g of a foam. This foam was purified by chromatography, giving 0.75 g of the desired product as a light yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[F:12][C:13]1[CH:14]=[C:15]([C:19]#[CH:20])[CH:16]=[CH:17][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:20]#[C:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: C#Cc1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2cccc(F)c2)cn1
Temperature: 80 °C
Reaction time: 20 h
Yield: 65.9 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (406 mg, 580 μmol, 0.05 equiv.) was dissolved in 25 ml DMF. (2.5 g, 11.6 mmol) 5-Bromo-pyridine-2-carboxylic acid methyl ester and 3-fluorophenylacetylene (2.22 g, 18.5 mmol, 1.6 equiv.) were added at room temperature. Triethylamine (3.5 g, 4.84 ml, 34.7 mmol, 3 equiv.), triphenylphosphine (91 mg, 347 μmol equiv.) and copper(I)iodide (66 mg, 347 μmol, 0.03 equiv.) were added and the mixture was stirred for 20 hours at 80° C. The reaction mixture was cooled and evaporated to dryness with Isolute® sorbent. The crude product was purified by flash chromatography on silica gel (70 g) eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid methyl ester (1.95 g, 66% yield) was obtained as a light yellow solid, MS: m/e=256.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[C:24]1C=CC([N+]([O-])=O)=NC=1.C(OC(N1CCN[C@@H](C)C1)=O)(C)(C)C>>[CH3:24][C@@H:15]1[N:10]([C:7]2[CH:8]=[N:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])nc1
Yield: 50 %

Procedure:
Following the procedures as described for compound 101g, reaction of 5-bromo-2-nitropyridine (10.5 g, 50 mmol), and (35)-tert-butyl-3-methylpiperazine-1-carboxylate (10.0 g, 50 mmol) afforded 130a as a yellow solid (8.05 g, 50%). LCMS: [M+H]+ 323
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH:7](C)[CH2:8][CH:9]=O.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>C(O)(=O)C.N1CCCCC1>[C:12](/[C:14](=[CH:9]\[CH2:8][CH2:7][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)/[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: CC(CC=O)c1cnccn1
Reactant: COC(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)/C(C#N)=C/CCc1cnccn1
Yield: 35.5 %

Procedure:
A solution of 13e (0.191 g, 1.27 mmol) in 0.17 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.115 g, 1.27 mmol, 0.1 mL, 1.0 equiv), then a premixed solution of piperidine (0.0038 g, 0.04318 mmol, 4.4 mL, 3.4 mol %) and 50 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 25-65% EtOAc/hexanes) afforded 15e (0.098 g, 0.282 g theoretical, 35%). For 15e: 1H NMR (CDCl3, 400 MHz) d 8.52 (dd, 1H, J=1.6, 2.5 Hz, Pyr C5-H), 8.46 (d, 1H, J=1.6 Hz, Pyr C3-H), 8.44 (d, 1H, J=2.5 Hz, Pyr C6-H), 7.59 (dd, 1H, J=7.8, 7.8 Hz, CH=C), 3.82 (s, 3H, OCH3), 3.23 (ddq, 1H, J=6.4, 7.0, 7.2 Hz, PyrCH), 3.07 (ddd, 1H, J=7.2, 7.8, 14.9 Hz, CHH), 2.91 (ddd, 1H, J=6.4, 7.8, 14.6 Hz, CHH), 1.39 (d, 3H, J=7.0 Hz, CH3); IR (neat) nmax 2967, 2360, 2341, 1737, 1626, 1437, 1407, 1282, 1259, 1060, 1017, 850, 761, 668 cm-. See FIG. 19d.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=O)(C)(C)C.[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:50]=[CH:49][C:46](C=O)=[CH:45][CH:44]=2)[CH:42]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CC(N(C)C)=O>[CH3:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][N:33]=[C:32]2[C:38]1[N:39]=[N:40][N:41]([C:43]2[CH:44]=[CH:45][C:46]([CH2:20][N:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]3)=[CH:49][CH:50]=2)[CH:42]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CC(=O)O
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCNCC5)cc4)nn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) was added to a solution of tert-butyl-1-piperazinecarboxylate (1.22 g; 6.59 mmol; 10 eq.) and 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) in DMA (4 mL) and the reaction mixture was stirred overnight at RT. Sodium triacetoxyborohydride (279 mg; 1.32 mmol; 2.0 eq.) and glacial acetic acid (75.42 μl; 1.32 mmol; 2.00 eq.) then sodium cyanoborohydride (83 mg; 1.32 mmol; 2. eq.) were added to complete the reaction which was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The resulting gum was stirred at RT in a solution of HCl in dioxane (5 mL, 4N) for 2 hours. The reaction mixture was basified to pH=9-10 and extracted with EtOAc. Organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a formic acid salt. It was dissolved in MeOH and passed through a SPE-NH2 cartridge. The fractions containing the desired compound were concentrated to dryness affording a yellow gum, which was twice sonicated in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to afford the title compound as a beige solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.23 (brs, 1H), 9.25 (s, 1H), 8.14-8.13 (m, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.28 (dd, J=8.5 Hz, 1.5 Hz, 1H), 3.52 (s, 2H), 2.72-2.69 (m, 4H), 2.487 (s, 3H), 2.32-2.30 (m, 4H). HPLC (Condition A): Rt 2.22 min (purity 95.4%). MS (ESI+): 374.3, MS (ESI−): 372.3.