Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=1[O:24][CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[C:33]([O:35]C(C)(C)C)=[O:34])=[O:27])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][O:24][C:17]1[C:18]([O:22][CH3:23])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])([OH:35])=[O:34]
Reactant: COc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1OCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1OCC(=O)N1CCC[C@@H]1C(=O)O
Reaction time: 8 h
Yield: 96.4 %

Procedure:
A solution of 345 mg (0.61 mmol) (R)-1-[[2-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-3-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 265 mg (96%) of the title compound as a white powder.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:45]=[CH:44][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][C:32]4[N:37]=[C:36]([C:38]5[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[CH:34][N:33]=4)[CH:25]=3)=[O:22])=[CH:19][CH:18]=2)[CH2:12][CH2:11]1.O>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([NH:31][C:32]4[N:37]=[C:36]([C:38]5[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=5)[CH:35]=[CH:34][N:33]=4)[CH:25]=3)=[O:22])=[CH:44][CH:45]=2)[CH2:12][CH2:11]1.[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5]
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: CCO
Solvent: O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 90 °C

Procedure:
(Trans)-butenedioic acid (fumaric acid; Fluka, Buchs, Switzerland; 1.16 g, 10 mmol) is added to a solution of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide (4.94 g, 10 mmol) in ethanol (25 mL). The mixture is heated to 90° C., treated with water (18 g) and filtered. Upon cooling, the product crystallizes and is filtered and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, fumarate a pale-yellow crystalline solid, having the following analytical properties: Analysis found: C, 63.91; H, 5.99; N, 15.74%; H2O, 1.27%. Calculated for C33H35N7O5-0.44 H2O: C, 64.18; H, 5.86; N, 15.88%; H2O, 1.28%.
Reaction SMILES: [C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].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>[C:1]1([Si:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([O:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[OH:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O[Si](O)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCCO[Si](O)(c1ccccc1)c1ccccc1

Procedure:
Diphenyl-cis-9-octadecenyloxysilanol is prepared under Mitsunobu conditions from 2 g (9.25 mmol) of diphenylsilanediol, 2.08 ml (4.62 mmol) of cis-9-octadecen-1-ol, 2.45 g (9.25 mmol) of triphenylphosphine and 1.88 ml (9.25 mmol) of azodicarboxylic acid diisopropyl ester in 40 ml of tetrahydrofuran analogously to Step 1.3, Variant a.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:18][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:16])([CH3:15])[CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)CCC(C)(C)CCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CCC(C)(C)CCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 9-hydroxy-4,4-dimethylnonanoate (example 285, step f) (0.44 g) in DCM (19 mL) at 0° C. was treated with carbon tetrabromide (0.76 g) followed by triphenylphosphine (0.60 g) and the reaction mixture was stirred at room temperature overnight. Further amounts of carbon tetrabromide (0.76 g) and triphenylphosphine (0.60 g) were added and stirring continued for 3 hours. The solvent was removed by evaporation then the mixture was triturated with cyclohexane and the resultant solid removed by filtration. The solid was washed with cyclohexane and the filtrate was concentrated to about 15 mL and left to stand overnight. The solid which came out of solution was removed by filtration, washed with cyclohexane and the filtrate evaporated to afford the subtitled compound as a pale brown oil. Yield 0.56 g.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=O)=O.[C:6]1([N:12]2[C:16](S)=[N:15][N:14]=[N:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>ClCCl>[C:6]1([N:12]2[C:16]([S:1][Cl:5])=[N:15][N:14]=[N:13]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Sc1nnnn1-c1ccccc1
Solvent: ClCCl
Product: ClSc1nnnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfuryl chloride (4.5 grams, 0.056 mol) was added dropwise at 10° C. to a mixture comprised of 10 grams (0.056 mol) of 1-phenyl-5-mercaptotetrazole and 100 ml of dichloromethane: The reaction mixture was then stirred for 2 hours at room temperature, after which the low boiling point compounds were removed by distillation under reduced pressure at a temperature of from 30° C. to 40° C. and 1-phenyltetrazol-5-sulfenyl chloride was obtained.
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][N:24]1[C:28]([CH2:29][C@H:30]([NH:34][C:35]([CH2:37][CH2:38]N)=[O:36])[C:31]([OH:33])=[O:32])=[CH:27][N:26]=[CH:25]1.[N+]([O-])(O)=O.[Cl:44][C:45]1[CH:46]=[C:47]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:48][N:49]([CH3:60])[C:50]([C:52]1[CH2:53][N:54](C)[C:55](=[O:58])[C:56]=1[OH:57])=[O:51]>>[Cl:44][C:45]1[CH:46]=[C:47]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:48][N:49]([CH3:60])[C:50]([C:52]1[CH2:53][N:54]([CH:29]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)[CH:30]([NH:34][C:35](=[O:36])[CH2:37][CH3:38])[C:31]([OH:33])=[O:32])[C:55](=[O:58])[C:56]=1[OH:57])=[O:51]
Reactant: Cn1cncc1C[C@H](NC(=O)CCN)C(=O)O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Solvent: O=[N+]([O-])O
Product: CCC(=O)NC(C(=O)O)C(c1cncn1C)N1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 1 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and L-anserine nitrate as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white solid (3.3 mg, 1% yield). 1H NMR (500 MHz, CDCl3) δ: 8.56 (s, 1H), 7.36 (d, 1H, J=8.24) 7.29 (m, 1H), 7.20 (s, 1H), 7.04 (m, 1H), 4.69 (m, 1H), 4.52 (s, 2H), 4.05 (s, 2H), 3.76 (s, 3H), 3.65 (t, 2H, J=5.80), 3.14 (m, 2H), 2.94 (s, 2H), 2.51 (m, 2H). HRMS (M+H) calcd for C23H26N5Cl2O6: 538.1260. found: 538.1280.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.Br[CH:18]([CH3:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[S:15][C:18]([CH3:27])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:16]=3)=[CH:11][CH:12]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Reactant: CC(Br)C(=O)c1ccccc1
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccccc4)c(C)s3)cc2)cn1
Yield: 94 %

Procedure:
Prepared in analogy to example 64d) from 100 mg (0.43 mmol) [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea and 101 mg (0.47 mmol) 2-bromopropiophenone. 140 mg (94%) of the product was isolated as a colorless solid. MS ISP (m/e): 347.1 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.48 (s, 1H), 9.46 (s, 1H), 7.93 (s, 1H), 7.88 (d, 2H), 7.69 (d, 2H), 7.47 (t, 2H), 7.36 (t, 1H), 2.46 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=[O:2].[OH-:21].[Na+]>C(O)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH3:18][C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:6]2[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)s2)CC1
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)s2)CC1
Temperature: 65 °C
Yield: 70.8 %

Procedure:
A solution of tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate (2.51 g, 8.50 mmol) in ethanol (85 ml) was added in one portion to a solution of silver (I) nitrate (10.0 g, 58.8 mmol) and sodium hydroxide (4.83 g, 120.6 mmol) in water (85 ml). This mixture was stirred and heated at 65° C. for 22 h. The mixture was cooled by the addition of ice and then filtered to remove silver salts. The filtrate was carefully evaporated to remove the ethanol and the resulting aqueous solution was filtered again through a glass-fibre pad to remove tarry material. The filtrate was then diluted with water to a total volume of 400 ml and then acidified to pH 5 with acetic acid. The precipitate was filtered off, washed with water and then dried in a vacuum oven at 45° C. overnight to give 5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]thiophene-2-carboxylic acid (1.88 g, 71%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:76]=[CH:77][C:78]=1[N+:79]([O-])=O)[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:52]3[CH:57]=[CH:56][C:55]([O:58][C:59]4[CH:64]=[CH:63][C:62]([N+:65]([O-])=O)=[C:61]([O:68]CC5C=CC=CC=5)[CH:60]=4)=[CH:54][CH:53]=3)[C:31]3[CH:30]=[C:29]([C:32]45[CH2:41][CH:36]6[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]6)[CH2:33]4)[CH2:39]5)[CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][C:22]([C:42]24[CH2:51][CH:46]5[CH2:47][CH:48]([CH2:50][CH:44]([CH2:45]5)[CH2:43]2)[CH2:49]4)=[CH:23][CH:24]=3)=[CH:15][CH:14]=1)C1C=CC=CC=1.C12(C3C=C(C45CC6CC(CC(C6)C4)C5)C(OC4C=CC([N+]([O-])=O)=C(OCC5C=CC=CC=5)C=4)=CC=3OC3C=CC([N+]([O-])=O)=C(OCC4C=CC=CC=4)C=3)CC3CC(CC(C3)C1)C2>>[NH2:65][C:62]1[CH:63]=[CH:64][C:59]([O:58][C:55]2[CH:56]=[CH:57][C:52]([C:19]3([C:16]4[CH:17]=[CH:18][C:13]([O:12][C:11]5[CH:76]=[CH:77][C:78]([NH2:79])=[C:9]([OH:8])[CH:10]=5)=[CH:14][CH:15]=4)[C:20]4[CH:21]=[C:22]([C:42]56[CH2:43][CH:44]7[CH2:50][CH:48]([CH2:47][CH:46]([CH2:45]7)[CH2:51]5)[CH2:49]6)[CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][C:29]([C:32]35[CH2:39][CH:38]6[CH2:37][CH:36]([CH2:35][CH:34]([CH2:40]6)[CH2:33]3)[CH2:41]5)=[CH:28][CH:27]=4)=[CH:53][CH:54]=2)=[CH:60][C:61]=1[OH:68]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C3(c4ccc(Oc5ccc([N+](=O)[O-])c(OCc6ccccc6)c5)cc4)c4cc(C56CC7CC(CC(C7)C5)C6)ccc4-c4ccc(C56CC7CC(CC(C7)C5)C6)cc43)cc2)cc1OCc1ccccc1
Agent: O=[N+]([O-])c1ccc(Oc2cc(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c(C34CC5CC(CC(C5)C3)C4)cc2C23CC4CC(CC(C4)C2)C3)cc1OCc1ccccc1
Product: Nc1ccc(Oc2ccc(C3(c4ccc(Oc5ccc(N)c(O)c5)cc4)c4cc(C56CC7CC(CC(C7)C5)C6)ccc4-c4ccc(C56CC7CC(CC(C7)C5)C6)cc43)cc2)cc1O
Yield: 88.7 %

Procedure:
Next, a synthesis was performed in the same condition as in Synthesis example 1 except that 50.2 g of the 9,9-bis(4-(3-benzyloxy-4-nitrophenoxy)-phenyl)-2,7-di(1-adamantyl)-fluorene obtained above (46.8 mmol) was used in place of 39.0 g of 4,6-di(1-adamantyl)-1,3-bis(3-benzyloxy-4-nitrophenoxy)benzene mmol), thus obtaining 34.6 g of 9,9-bis(4-(4-amino-3-hydroxyphenoxy)-phenyl)-2,7-di(1-adamantyl)-fluorene (41.5 mmol; yield: 88.7%).
Reaction SMILES: CC(C)([O-])C.[K+].O[CH:8](S([O-])(=O)=O)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:23])[CH:12]=1.[Na+].[C:29]([O:33][C:34](=[O:48])[CH2:35][CH:36](P(OCC)(OCC)=O)[C:37]([OH:39])=[O:38])([CH3:32])([CH3:31])[CH3:30].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[OH-].[Na+].[CH:64]1([NH2:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1>C1COCC1.C(O)(C)(C)C.O>[CH:64]1([NH2:70])[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.[C:29]([O:33][C:34](=[O:48])[CH2:35]/[C:36](=[CH:8]\[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:23])[CH:12]=1)/[C:37]([OH:39])=[O:38])([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1cc(CCC(O)S(=O)(=O)[O-])ccc1-c1ccccc1
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CC/C=C(\CC(=O)OC(C)(C)C)C(=O)O)ccc1-c1ccccc1
Temperature: -2.5 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of potassium tert-butoxide (6.6 Kg, 59 mol) in THF (22 liters) was added over 1 hour to a stirred solution of sodium 1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (4.55 Kg, 13.8 mol) and 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (4.94 Kg, 15.9 mol) in THF (5.2 liters) and tert-butanol (18.3 liters), from −5 to 0° C., under nitrogen. The mixture was stirred from −5 to 0° C. for 4 hours and then a solution of citric acid (12.0 Kg, 62 mol) in demineralised water (28 liters) was added in one portion. The pH was adjusted to pH4-5 by the addition of aqueous sodium hydroxide solution (40%) and the organic phase was separated. The organic phase was concentrated in vacuo to a volume of approximately 25 liters and then recombined with the aqueous phase. Ethyl acetate (28 liters) was added and the organic phase was separated and then washed with a solution of sodium bicarbonate (3.18 Kg) in demineralised water (45 liters). Demineralised water (15 liters) was added and the pH was adjusted to pH 4-5 by the addition of a solution of citric acid (2.27 Kg) in demineralised water (23 liters). The organic phase was separated, washed with demineralised water (14 liters) and then azeotropically dried by distillation at atmospheric pressure at a constant volume of 56 liters. The reaction was cooled to 35 to 40° C. and cyclohexylamine (1.10 Kg, 11.1 mol) was added in one portion. The mixture was cooled to 20-25° C. and was stirred for 18 hours. The mixture was then cooled to 0° C., and was stirred for 2 hours and then filtered. The residue was washed with ethyl acetate (5 liters), then dried in vacuo at 40-45° C. to leave the title compound as a colourless solid (4.1 Kg, 61% yield, 89% pure by HPLC).
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:42]=[CH:41][C:28]([CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:27][CH:26]=2)O1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:25]3[CH:42]=[CH:41][C:28]([CH2:29][NH:30][C:31](=[O:40])[O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:27][CH:26]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1ccc(-n2cnc(Br)n2)cc1
Reactant: CC1(C)OB(c2ccc(CNC(=O)OCc3ccccc3)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Product: O=C(NCc1ccc(-c2ncn(-c3ccc(C(F)(F)F)cc3)n2)cc1)OCc1ccccc1

Procedure:
The title compound was prepared as described in Example 10 using 3-bromo-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole (C1b), benzyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (C13), tri-tert-butylphosphonium tetrafluoroborate, palladium(II) acetate, and cesium fluoride and isolated as a white solid (0.846 g, 36%): 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.28-8.14 (m, 2H), 8.16-8.04 (m, 2H), 8.04-7.95 (m, 2H), 7.92 (t, J=6.2 Hz, 1H), 7.49-7.13 (m, 7H), 5.07 (s, 2H), 4.29 (d, J=6.2 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −60.79; ESIMS m/z 453 ([M+H]+).
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:30]1[CH:35]=[CH:34][C:33]([N:36]([CH3:39])[CH:37]=[O:38])=[CH:32][CH:31]=1>>[CH:37]([N:36]([CH3:39])[C:33]1[CH:34]=[CH:35][C:30]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH2:16][NH:15][CH:12]3[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]3)[CH:18]=2)=[CH:31][CH:32]=1)=[O:38]
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CN(C=O)c1ccc(Br)cc1
Product: COc1ccc(-c2ccc(N(C)C=O)cc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (260 mg, 0.66 mmol) is coupled to aryl bromide 51 (170 mg, 0.79 mmol) using Method B to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:30]C)[CH:26]=4)[C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].Br.C(=O)([O-])O.[Na+].CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>O1CCOCC1.O>[C:1]([O:5][C:6](=[O:34])[N:7]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[C:25]([OH:30])[CH:26]=4)[C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C(=O)OC(C)(C)C)C3)c(F)c1)C2=O
Agent: Br
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ccc(N3CCc4cc(O)ccc4C3=O)cc2F)C1

Procedure:
According to Method L, {(R)-1-[2-fluoro-4-(6-methoxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester was treated with hydrogen bromide. The raw product (5.5 g) was dissolved in 1,4-dioxan (50 mL) and water (50 mL), sodium hydrogencarbonate (2.6 g) and lastly Boc2O (3.38 g) were added. After 3 hours the 1,4-dioxan was removed in the rotary evaporator and the residue was distributed between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. In this way the product was obtained with molecular weight 455.53 (C25H30FN3O4); MS (ESI): 456 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]#[N:16].C(=O)([O-])[O-:18].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:16])=[O:18]
Reactant: N#Cc1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolved 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carbonitrile in DMSO (40 mL), added potassium carbonate (0.50 eq., 2.59 g), then added hydrogen peroxide solution (3.5 mL of 30% solution in H2O) dropwise over ice bath over the course of 10 minutes. After the final addition, kept on ice bath for 2 hrs, then heated to room temperature and stirred until complete by TLC. After 24 hrs, reaction had not come to completion, so the amount of hydrogen peroxide was doubled (additional 3.5 mL). Still incomplete, though progressing, the reaction was stirred at room temperature over the weekend. Reaction was complete by TLC after 3 days of stirring and was poured into 350 mL of ice water. After precipitate formed, solution was filtered and washed with water to obtain 5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide as a gray powder as product.
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH:14]=[CH2:15])[CH3:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1>O1CCCC1.C1C=CC=CC=1>[CH2:10]([O:12][CH:13]([O:16][CH2:17][CH3:18])[CH2:14][CH2:15][C:28]1[CH:37]=[N:36][C:31]2=[N:32][CH:33]=[CH:34][N:35]=[C:30]2[CH:29]=1)[CH3:11]
Reactant: Brc1cnc2nccnc2c1
Reactant: C=CC(OCC)OCC
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCOC(CCc1cnc2nccnc2c1)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 9-BBN (10.2 mL of a 0.5M solution in tetrahydrofuran) at 0° C. was added dropwise 0.77 mL of acrolein diethyl acetal and the mixture allowed to warm slowly to room temperature. After 15 hours, the mixture was diluted with 12 mL dry tetrahydrofuran followed by the sequential addition of potassium phosphate (1.6 g), palladium(1,1'-bis(diphenylphosphino)ferrocenyl) dichloride (160 mg) and 7-bromo-pyrido[2,3-b]pyrazine (924 mg) and then heated to reflux on an oil bath. After 5 hours, the mixture was cooled to 0° C., diluted with 15 mL benzene and the excess reagents quenched by the addition of 2N sodium hydroxide (3.5 mL) and 30% hydrogen peroxide (2.5 mL). The mixture then extracted with ethyl acetate, washed with brine and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:4; then 1:1; then 4:1) to give the title compound (1.2 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH:21]=2)[OH:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:2]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2=CCCc3ccccc32)c(C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)c2cccc3ccccc23)c(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Manganese dioxide (390 mg, 4.5 mmol) is added to a solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(3,4-dihydro-naphthalen-1-yl)-methanol (63 mg, 0.15 mmol) in dichloromethane (10 mL). The mixture is stirred overnight at room temperature. The mixture is filtered on celite and the filtrate concentrated and chromatographed on silica gel to give [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-naphthalen-1-yl-methanone. 1H NMR (CDCl3) 9.22 (d, 1H), 8.09 (d, 1H), 7.95 (d, 1H), 7.74 (t, 2H), 7.62 (t, 1H), 7.50 (t, 1H), 7.32 (t, 1H), 7.18 (d, 2H), 6.77 (s, 1H), 3.69 (s, 3H), 2.50-2.42 (m, 4H), 2.47 (s, 3H), 1.14 (t, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7](OCC)=[O:8].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[C:6]([CH:7]=[O:8])[CH:5]=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cncc(F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1cncc(F)c1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
To a mixture of 3.5 g of ethyl 5-fluoronicotinate (21 mmol) in 80 mL of dry toluene at −78° C. under nitrogen was added 42 mL of 1.0M DIBAL in toluene dropwise with stirring. The mixture was stirred at −78° C. for 3 h and the excess DIBAL was quenched by adding 0.5 mL of EtOAc. The mixture was allowed to warm to room temperature and 100 mML of water was added. The mixture was filtered through celite and the filter cake washed with 3×10 mL of toluene. The layers were separated and the organic phase was washed with brine, dried (MgSO4) and loaded onto a column (silica gel). The product was purified by eluting with 20%-35% EtOAc in hexanes to give 700 mg of 5-fluoro-3-pyridinecarboxaldehyde and 2.0 g of un-reacted starting material.