Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:3]=1>[Ni]>[F:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: N#Cc1cc(F)c(F)cc1Oc1ccccn1
Agent: [Ni]
Product: NCc1cc(F)c(F)cc1Oc1ccccn1

Procedure:
The product of Example 136B and Raney/nickel were processed according to the method of Example 131C to provide the product. MS (ESI+) m/z 237 (M+H)+;
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:49]=2)[C:44]1=[O:56])(=O)C>>[C:52]([C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[C:44](=[O:56])[N:43]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:28]=1[CH2:27][OH:26])[CH2:51]2)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCOCC3)cc2)c1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)nc(Nc2ccc(N3CCOCC3)cc2)c1=O
Yield: 47 %

Procedure:
Using the same general procedure as Example 105, reaction of 108a (296 mg, 0.810 mmol) with 103f (413 mg, 0.891 mmol) afforded 108 in 47% yield (205 mg) as an amorphous yellow solid: mp 225-227° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.58 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.42 (dd, J=8.0, 1.0 Hz, 1H), 7.34 (s, 1H), 6.89 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), 4.83 (t, J=5.0 Hz, 1H), 4.43 (d, J=5.0 Hz, 2H), 3.72 (t, J=5.5 Hz, 4H), 3.54 (s, 3H), 3.03 (t, J=5.5 Hz, 4H), 1.37 (s, 9H); MS (ESI+) m/z 580.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:27]([N:30]([CH2:34][CH:35]1[CH:40]([NH2:41])[CH:39]2[CH2:42][CH2:43][N:36]1[CH2:37][CH2:38]2)[CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:41][CH:40]1[CH:39]2[CH2:42][CH2:43][N:36]([CH2:37][CH2:38]2)[CH:35]1[CH2:34][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])=[O:9]
Reactant: CNc1cc(OC)c(C(=O)O)cc1Cl
Reactant: CCCN(CCC)CC1C(N)C2CCN1CC2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCN(CCC)CC1C(NC(=O)c2cc(Cl)c(NC)cc2OC)C2CCN1CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
A solution of 5-chloro-2-methoxy-4-(methylamino)benzoic acid (3.35 g, 15.5 mmoles) in anhydrous tetrahydrofuran (20 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (2.56 g, 15.8 mmoles), and stirred for one hour at room temperature. Nitrogen was bubbled through the solution for 20 minutes, and a solution of 2-(di-n-propylaminomethyl)-1-azabicyclo[2.2.2]-octan-3-amine (3.95 g, 15.8 mmoles) in tetrahydrofuran (10 ml) was added dropwise. The mixture was maintained at room temperature for 18 hours, and at 50° C. for 1 hour, then concentrated in vacuo. The residue was partitioned between methylene chloride and 1.0N aqueous sodium carbonate, and the organic layer was separated. The aqueous solution was extracted with methylene chloride, and the combined organic solution was dried (Na2SO4) and concentrated in vacuo. The residue was filtered through alumina (eluted with 3% methanol/methylene chloride) to provide 5.38 g (79%) of a colorless foam.
Reaction SMILES: [C:1]1([C:17](O)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[NH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:51]1[CH2:65][CH2:64][CH2:63][N:62]([S:66]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=2[N+:75]([O-:77])=[O:76])(=[O:68])=[O:67])[CH2:61][C:60]2[N:78]=[C:56]([CH:57]=[CH:58][CH:59]=2)[CH2:55][N:54]([S:79]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=2[N+:88]([O-:90])=[O:89])(=[O:81])=[O:80])[CH2:53][CH2:52]1>C1COCC1>[C:1]1([C:17]([NH:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][N:51]2[CH2:65][CH2:64][CH2:63][N:62]([S:66]([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][C:70]=3[N+:75]([O-:77])=[O:76])(=[O:67])=[O:68])[CH2:61][C:60]3[N:78]=[C:56]([CH:57]=[CH:58][CH:59]=3)[CH2:55][N:54]([S:79]([C:82]3[CH:87]=[CH:86][CH:85]=[CH:84][C:83]=3[N+:88]([O-:90])=[O:89])(=[O:81])=[O:80])[CH2:53][CH2:52]2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: NCCCCCN1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(NCCCCCN1CCCN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cccc(n2)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])CC1)c1ccc2ccc3cccc4ccc1c2c34
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
A solution of 1-pyrenecarboxylic acid (0.22 g, 0.89 mmol) and 4-methymoroholine (0.12 g, 1.14 mmol) in 5 mL of anhydrous THF was stirred for 30 min. After addition of DCC (0.16 g, 0.76 mmol) and HOBT (0.11 g, 0.76 mmol), the solution was stirred another 30 min. A solution of 6-(5-amino-1-pentanyl)-3,10-bis(2-nitrobenzenesulfonyl)-3,6,10,16-tetraazabicyclo[10.3.1]hexadeca-1(16),12,14-triene (0.51 g, 0.76 mmol) was added into the above solution and stirred at rt overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2. The resulting solution was washed with 5% NaHCO3 solution and brine, dried and concentrated. The residue was purified by flash chromatography on a silica gel column using 100:1 CH2Cl2—MeOH as an eluent to give 0.45 g (65%) of the title compound as a yellow foam.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[N:9]2[CH:18]=[C:19]([F:21])[CH:20]=[C:8]2[C:7]=1[OH:22])=O)C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=1[S:31]([NH2:34])(=[O:33])=[O:32].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:8]2[C:7]([OH:22])=[C:6]([C:4]3[NH:23][C:24]4[CH:29]=[CH:28][C:27]([I:30])=[CH:26][C:25]=4[S:31](=[O:33])(=[O:32])[N:34]=3)[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[N:9]2[CH:18]=1
Reactant: Nc1ccc(I)cc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2cc(F)cn2n(CCC(C)C)c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(I)ccc3N2)c(O)c2cc(F)cn21
Temperature: 120 °C
Yield: 19.5 %

Procedure:
6-Fluoro-4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 14i, 136.7 mg, 0.441 mmol) and 2-amino-5-iodo-benzenesulfonamide (Example 4a, 131.3 mg, 0.441 mmol) were mixed in anhydrous pyridine (2 mL) and heated at 120° C. for 3 h. 1,8-Diazabicyclo[5.4.0]undec-7-ene (200 μL) was added and the mixture was heated at 120° C. for 16 h. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm, 20% ethyl acetate in hexanes) afforded the desired product, 6-fluoro-4-hydroxy-3-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(3-methyl-butyl)-pyrrolo[1,2-b]pyridazin-2-one (0.047 g, 0.086 mmol, 19.5% yield) as a dark purple solid. LC-MS (ESI) calcd for C19H18FIN4O4S 544.01, found 544.97 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1.I[CH2:33][CH2:34][OH:35].C([O-])([O-])=O.[Cs+].[Cs+].CN1C(=O)CCC1>CCOC(C)=O>[CH3:1][C:2]1([CH3:31])[N:6]([C:7]2[S:8][C:9]3[CH:15]=[C:14]([CH2:16][N:17]4[C:21]5[CH:22]=[CH:23][C:24]([O:26][CH2:33][CH2:34][OH:35])=[CH:25][C:20]=5[N:19]=[CH:18]4)[CH:13]=[CH:12][C:10]=3[N:11]=2)[C@@H:5]2[CH2:27][CH2:28][CH2:29][CH2:30][C@H:4]2[O:3]1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(O)ccc43)cc2s1
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cc(OCCO)ccc43)cc2s1
Temperature: 100 °C
Yield: 38.8 %

Procedure:
A stirred mixture of 1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-ol (60 mg, 0.14 mmol) from Step 1 of Example 171, 2-iodoethanol (60 mg, 0.35 mmol), Cs2CO3 (137 mg, 0.42 mmol), and NMP (2 mL) was heated at 100° C. for 24 h. The mixture was diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC to afford 2-((1-((2-((3aR,7aR)-2,2-dimethylhexahydrobenzo[d]oxazol-3(2H)-yl)benzo[d]thiazol-6-yl)methyl)-1H-benzo[d]imidazol-5-yl)oxy)ethanol (26 mg, 39%) as a light yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.40 (s, 1H), 7.32 (s, 1H), 7.16-7.19 (m, 2H), 6.91 (m, 1H), 5.36 (s, 2H), 4.13 (t, J=9.0 Hz, 2H), 3.98 (t, J=9.0 Hz, 2H), 3.65 (m, 1H), 3.08 (m, 1H), 2.80 (m, 1H), 2.14 (m, 1H), 1.84-1.92 (m, 2H), 1.78 (s, 3H), 1.63 (s, 3H), 1.28-1.40 (m, 4H); LCMS (ESI) m/z 479 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]#[N:21])[CH:8]=2)=[N:3][CH:2]=1.O.S(=O)(=O)(O)[OH:24].N>C(O)(C(F)(F)F)=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:11][C:10]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[CH3:19])=[C:9]([C:20]([NH2:21])=[O:24])[CH:8]=2)=[N:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C#N
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1ccc(Cl)cc1-c1[nH]c(-c2ccncn2)cc1C(N)=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
To a solution of 5-(pyrimidin-4-yl)-2-(5-chloro-2-methyl-phenyl)-1H-pyrrole-3-carbonitrile (85 mg, 0.28 mmol) in TFA (1.0 mL) were sequentially added water (0.15 mL) and 98% sulfuric acid (0.30 mL) under efficient stirring. The mixture was allowed to stir for 5 h at 70° C. and then was diluted by drop wise addition of water (1 mL). The reaction mixture was made basic (pH 10-12) by adding 30% aqueous ammonia (3 mL) under stirring. The precipitated solid was collected by filtration, washed with water and finally dried in a vacuum oven at 50° C. affording the title compound (72 mg, 83%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6]>ClCCl>[CH2:5]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N+:1]([O-:4])=[O:2])[C:15]=1[OH:16])[CH:11]=[O:12])[CH3:6]
Reactant: CCOc1cc(C=O)ccc1O
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Temperature: 3 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (22.0 mL) was added (rate approx. 1.5 mL/min) to a stirred solution of 3-ethoxy-4-hydroxybenzaldehyde (83.0 g) in dichloromethane (400 mL) at 5°-10° C. Thereafter the mixture was stirred for 30 min at 3° C. and then filtered. The product was washed with dichloromethane and water and dried in vacuo at 50° C., yield 77.8 g (73,7%).
Reaction SMILES: CO[C:3]([C:5]1[N:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:8]=[C:7]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:6]=1)=[O:4].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CO>[O:37]1[CH2:38][CH2:39][N:34]([C:3]([C:5]2[N:10]=[C:9]([N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH:17]=3)[N:8]=[C:7]([NH:27][C:28]3[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=3)[CH:6]=2)=[O:4])[CH2:35][CH2:36]1
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Reactant: C1COCCN1
Solvent: CO
Product: Cc1cc(Nc2cc(C(=O)N3CCOCC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (200 mg, 0.45 mmol) and morpholine (0.5 ml, 5.73 mmol) in anhydrous methanol (5.0 ml) was heated at 120° C. for 18 hours. The volatiles were removed by evaporation and the residue was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through a 50 g isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation and the residue was triturated with diethylether. The resulting solid was collected by filtration to give the title compound (120 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=O)[C:5]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:6]1[C:5]([O:9][C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])=[CH:4][N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)[nH]c2=O)cc1C
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2Cl)cc1C
Temperature: 110 °C
Yield: 88 %

Procedure:
A mixture of 2-amino-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-3H-pyrimidin-4-one in phosphorus oxychloride (5 ml) was heated at 110° C. for 40 minutes and stirred at room temperature over night. Solvent was removed under reduced pressure and ice water was added. The aqueous solution was basified with potassium carbonate to pH 9, and extracted with methylene chloride. The organic phase was washed with brine and dried over anhydrous sodium sulfate. After removal of drying agent, the organic solution was concentrated under reduced pressure to yield 4-chloro-5-(2-isopropyl-4-methoxy-5-methyl-phenoxy)-pyrimidin-2-ylamine as yellow solid (0.043 g, 88%). MS M+H=308.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.Cl.[CH3:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)[CH3:30]>>[CH3:28][N:29]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]3[C:8]4[C:9]([NH:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=4[S:14][C:4]=3[CH:3]=2)=[CH:34][CH:33]=1)[CH3:30]
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Reactant: CN(C)Cc1ccc(B(O)O)cc1
Agent: Cl
Product: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(CN(C)C)cc5)ccc4c23)cc1

Procedure:
The title compound was prepared by the method described in Example 19, Step 1 using 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile Example 12, Steep 9) and {4-[(dimethylamino)methyl]phenyl}boronic acid hydrochloride.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[C:22]([F:34])[C:23]([CH:30](O)[CH2:31][CH3:32])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[C:18]=1[F:35])[CH2:13][CH2:14][CH3:15].O>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[CH2:12]([O:16][C:17]1[CH:29]=[CH:28][C:27]2[C:26]3[C:21](=[C:22]([F:34])[C:23]([CH2:30][CH2:31][CH3:32])=[CH:24][CH:25]=3)[CH2:20][C:19]=2[C:18]=1[F:35])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCOc1ccc2c(c1F)Cc1c-2ccc(C(O)CC)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc2c(c1F)Cc1c-2ccc(CCC)c1F
Reaction time: 3 h

Procedure:
After the addition of approx. 0.5 g of 4-toluenesulfonic acid and a few drops of concentrated sulfuric acid, a solution of 14 mmol of 2-butoxy-1,8-difluoro-7-(1-hydroxypropyl) fluorene in 50 ml of toluene is heated on a water separator for 3 h. After cooling, the mixture is extracted using 5 percent sodium hydrogencarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. Then 0.5 g of palladium catalyst (10 percent on activated carbon) are subsequently added and the mixture is hydrogenated at room temperature. The reaction mixture is filtered and the solvent is removed under reduced pressure. The crude product is purified by chromatography on silica gel and recrystallization from heptane. 2-Butoxy-1,8-difluoro-7-n-propylfluorene is obtained.
Reaction SMILES: [Na+].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O-:15])=[O:14])=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Cl>CN(C)C=O>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:14][C:13](=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:2][CH:3]([CH3:5])[CH3:4])=[CH:11][CH:10]=1
Reactant: ClCc1ccccc1Cl
Reactant: CC(C)Cc1ccc(CC(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(CC(=O)OCc2ccccc2Cl)cc1
Yield: 73.4 %

Procedure:
To a solution of 3.5 g of p-isobutylphenylacetic acid sodium salt in 20 ml of dimethylformamide was added 5.9 g of o-chlorobenzyl chloride, and the mixture was heated under reflux for 5 hours. After the reaction was complete, the mixture was cooled to produce an inorganic substance, which was then removed by filtration. The filtrate was freed of dimethylformamide by distillation in vacuo to give an oily product. Distillation of this product in vacuo yielded 3.8 g of p-isobutylphenylacetic acid-2-chlorobenzyl ester as a colorless oil, boiling at 145°-147° C/1 mmHg. Analysis-Calculated for C19H21ClO2 : C, 72.03; H, 6.68. Found: C, 71.98; H, 6.51. Mass spectrum: parent ion 316 m/e.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][CH:13]1[CH2:18][C@H:17](O)[C@@H:16]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:15]2[CH:16]([CH:20]([CH3:22])[CH3:21])[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CC1CC[C@H](C(C)C)[C@@H](O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)Cc2ccc(O)cc2)C1

Procedure:
2.9 kg of p-hydroxyphenylacetic acid and 1.95 kg of (+)-menthol are heated to boiling for 16 hours with 40 g of p-toluenesulphonic acid in 25 l of toluene; about 300 ml of water are separated in this process. The toluene solution is washed with 10 l of saturated NaHCO3 solution and 10 l of water and concentrated to dryness in vacuo. The title compound is obtained as 5.4 kg of oily residue (98-100% of theory) having a purity of 91.8% (HPLC surface area percentage). For analytical purposes, the (+)-menthylhydroxyphenylacetate was recrystallised twice from n-hexane.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:23]([OH:25])=[O:24])=[C:5]([C:7]2[C:17]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:16]=3[O:15][C:14]3[C:8]=2[CH:9]=[CH:10][C:11]([CH:13]=3)=[O:12])[CH:6]=1.[CH3:26][O:27]CCl>CS(O)(=O)=O>[OH:27][CH2:26][C:13]1[C:14]2[O:15][C:16]3[C:17](=[CH:18][CH:19]=[C:20]([OH:22])[CH:21]=3)[C:7]3([C:5]4[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=4)[C:23](=[O:25])[O:24]3)[C:8]=2[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: COCCl
Reactant: O=C(O)c1ccccc1-c1c2ccc(=O)cc-2oc2cc(O)ccc12
Agent: CS(=O)(=O)O
Product: O=C1OC2(c3ccc(O)cc3Oc3c2ccc(O)c3CO)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.8 %

Procedure:
To a solution of 50 mg (0.15 mmol) of fluorescein in 0.3 mL of methanesulfonic acid was added 13 μL (0.16 mmol) of chloromethyl methyl ether at room temperature. The mixture was stirred at room temperature for 48 hours. The reaction mixture was poured into 10 mL of ice-cold water. A yellow-orange solid precipitated out and was filtered. The crude product was purified by preparative thin layer chromatography (silica gel, 2 mm) using 8:1:1 chloroform:methanol:toluene to yield 20 mg (37%) of rac-4'-(hydroxymethyl)-3',6'-dihydroxyspiro[isobenzofuran-1(3H),9'-[9H]xanthen]-3-one (2). NMR, IR and MS data confirmed the identity of the compound. To confirm the structural identity of compound (2), the compound was derivatized to the corresponding triacetate. NMR and MS data confirmed the identity of the triacetate. Hydrolysis of the triacetate yielded compound (2).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[C:18]([CH3:20])[O:17][N:16]=3)[N:4]2[N:3]=1.[N:21]1([CH:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][OH:34])=[N:31][CH:32]=2)[CH3:26])[CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH:25]([C:27]2[CH:28]=[CH:29][C:30]([CH2:33][O:34][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]4=[N:12][N:13]=[C:14]([C:15]5[CH:19]=[C:18]([CH3:20])[O:17][N:16]=5)[N:4]4[N:3]=3)=[N:31][CH:32]=2)[CH3:26])[CH2:24][CH2:23][CH2:22]1
Reactant: CC(c1ccc(CO)nc1)N1CCC1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C(C)N5CCC5)cn4)nn23)no1

Procedure:
The reaction was carried out as described in Example 1, Step 4 using 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (100 mg, 0.35 mmol) and [5-{1-(azetidin-1-yl)ethyl}pyridin-2-yl]methanol (67 mg, 0.35 mmol) to give, after column chromatography on silica, eluting with 2.5% MeOH/CH2Cl2 containing 1% NH3 solution, the amine (121 mg, 79%) which was recrystallised from CH2Cl2/hexane.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH:23]([CH2:25]O)[OH:24]>O>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH2:25][CH:23]([OH:24])[CH2:22][OH:21])=[O:19]
Reactant: OCC(O)CO
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(O)CO
Temperature: 50 °C

Procedure:
A mixture of oleic acid (1.5 g=5.32 mmoles), glycerol (0.57 g=6.2 mmoles), water (70 μl) and potato protein extract (100 mg) was stirred at 50° C. and a vacuum (<50 mbar) was applied to the system using an oil pump to remove water from the mixture. For comparison a similar reaction was run without vacuum in a stoppered tube. Samples were taken from the reaction mixtures periodically for analysis by GC. Progress curves for the reactions are given in FIG. 2. In the reaction cariied out under vacuum 4.43 mmoles of MG and 0.10 mmoles of DG were formed after 72 hours. 87% of the oleic acid was converted into acylglycerols. In the comparison reaction after 72 hours 3.51 mmoles of MG and 0.14 mmoles of DG were formed. The final conversion of oleic acid into acylglycerols was 71%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]3[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.9 %

Procedure:
To a mixture of 4-benzyloxy-phenyl-acetohydroximoyl chloride (140 mg, 0.51 mmol) described in Manufacturing Example 1-1-3 and tetrahydrofuran (10 mL) were added 3-ethynyl-pyridin-2,6-diamine (102 mg, 0.76 mmol) described in Manufacturing Example 13-1-3 and triethylamine (0.71 mL, 5.1 mmol), which was stirred overnight at room temperature. The reaction mixture was then stirred for further 1.5 hours at 55° C. The reaction solution was cooled to room temperature and concentrated under a reduced pressure. The residue was filtered by NH silica gel column chromatography (ethyl acetate) to obtain a crude product. The crude product was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid). The solvent was evaporated under a reduced pressure, and the residue was filtered with NH silica gel to obtain the title compound (51 mg, 27%).