Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:18]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][N:20]1[CH2:21][CH2:22][N:23]([C:26]2[CH:27]=[C:28]([NH:29][C:2]3[N:18]=[C:5]4[C:6]([NH:10][CH2:11][C:12]5[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)[CH:30]=[CH:31][CH:32]=2)[CH2:24][CH2:25]1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Reactant: Clc1nc2c(NCc3cccnc3)cccn2n1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(NCc5cccnc5)cccn4n3)c2)CC1

Procedure:
N(2)-[3-(4-Methyl-piperazin-1-yl)-phenyl]-N(8)-pyridin-3-ylmethyl-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-pyridin-3-ylmethyl-amine (75.0 mg, 0.289 mmol) and 3-(4-methylpiperazin-1-yl)aniline (61.0 mg, 0.319 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (33.0 mg, 0.0604 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.017 g, 14%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.66 (s, 1H), 8.56 (d, J=4.6 Hz, 1H), 7.85 (d, J=6.6 Hz, 1H), 7.72 (d, J=7.9 Hz, 1H), 7.31-7.25 (m, 1H), 7.24-7.18 (m, 2H), 7.06 (d, J=7.9 Hz, 1H), 6.75 (s, 1H), 6.68 (t, J=7.3 Hz, 1H), 6.57 (d, J=8.3 Hz, 1H), 6.32 (d, J=7.8 Hz, 1H), 5.18 (t, J=5.5 Hz, 1H), 4.51 (d, J=5.7, 2H), 3.28-3.23 (m, 4H), 2.61-2.56 (m, 4H), 2.36 (s, 3H). MS=415 (MH)+.
Reaction SMILES: S(Cl)(Cl)=[O:2].[CH3:5][C:6]1[NH:11][C:10]([C:12]([O-])=O)=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:7]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[CH3:34][NH:35][CH3:36]>C(Cl)Cl.CN(C)C=O.C1C=CC=CC=1>[CH3:34][N:35]([CH3:36])[C:12]([C:10]1[NH:11][C:6]([CH3:5])=[C:7]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:9]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:2]
Reactant: CCOC(=O)C1=C(C)NC(C(=O)[O-])=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CNC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(C(=O)N(C)C)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.05 ml) was added to a solution of 3,5-diethyl 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2,3,5-pyridinetricarboxylate (0.25 g, 0.62 mmoles) in methylene chloride (10 ml) containing dimethylformamide (1 drop). After 2 hours at room temperature further thionyl chloride (0.05 ml) was added and the solution was refluxed for 30 mins. After cooling to room temperature 10% dimethylamine in benzene (1 ml) was added and the mixture stirred for 30 mins. The solvent was evaporated and the residue dissolved in dilute hydrochloric acid and ether. The organic extract was washed with brine, dried (Na2SO4) and the solvent removed in vacuo to leave the title compound (0.2 g). M+ 431; nmr (CDCl3) δ 5.12 (s,H), 3.05 (s,3H), 2.95 (s,3H).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](/[C:24](/[CH3:31])=[CH:25]/[C:26](OCC)=[O:27])=[CH:20][CH:19]=1.Cl>C1COCC1.CO>[Br:17][C:18]1[CH:19]=[CH:20][C:21](/[C:24](/[CH3:31])=[CH:25]/[CH2:26][OH:27])=[CH:22][CH:23]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(Br)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: C/C(=C\CO)c1ccc(Br)cc1
Reaction time: 1 h

Procedure:
A 1M solution of DIBAL-H in toluene (42 ml, 42 mmol) was added dropwise, at −70° C. over 30 min, to a stirred solution of (E)-ethyl 3-(4-bromophenyl)-but-2-enoate (4.55 g, 16.92 mmol) in dry THF (100 ml), and the mixture stirred for 1 h. Methanol (5 ml) was carefully added, followed by 1N HCl (300 ml) and the resulting mixture extracted with ethyl acetate (3×200 ml). The combined organic extracts were washed with brine, dried (Na2SO4), and evaporated to give the crude product as an off-white solid, which was purified by recrystallisation from hot 1:4 ether/n-heptane (250 ml) to give the product (E)-3-(4-bromophenyl)-but-2-en-1-ol as colourless needles: 3.10 g (81%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:14][C:15](=O)[NH:16][C:17]1[S:21][C:20]2[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:19]=2[CH:18]=1)C1C=CC=CC=1>>[CH3:27][O:26][C:25]1[C:19]2[CH:18]=[C:17]([NH:16][C:15]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:14])[S:21][C:20]=2[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(NC(=O)OCc3ccccc3)cc12
Reactant: C1CCNCC1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)N3CCCCC3)cc12

Procedure:
The title compound MS: m/e=365.1 (M−H) was obtained as a light brown solid (62% yield) by the reaction of piperidine with (4-methoxy-7-phenyl-benzo[b]thiophen-2-yl)-carbamic acid benzyl ester according to the method described above for example 1.
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[H][H]>CO.[Pd]>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([NH:9][C@H:10]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCC(=O)N1)C(=O)N1CCC[C@@H]1C(N)=O
Yield: 79.1 %

Procedure:
1.5 g (3.25 mmoles) of Z-Glp-Leu-D-Pro-NH2 are dissolved in 70 ml of methanol, 0.3 g of a 10% palladium-on-carbon catalyst are added to the solution, and hydrogen is bubbled through the mixture for one hour. The catalyst is filtered off, the filtrate is evaporated, and the amorphous residue is triturated with ether. The resulting 0.94 g of crude product are dissolved in water, the solution is decolourized, filtered, and the clear filtrate is freeze-dried. 0.87 g (79%) of Glp-Leu-D-Pro-NH2 are obtained; Rf5 =0.47, [α]D25 =+8.4° (c=1%, in acetic acid).
Reaction SMILES: [OH-:1].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26]C(C#N)=[CH:24][CH:23]=3)[C:20]=1[CH3:21])=[O:15])[CH2:10]2.[O:30]1[CH2:35][CH2:34]OCC1>>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:22]3[CH:27]=[CH:26][C:34]([C:35]([OH:30])=[O:1])=[CH:24][CH:23]=3)[C:20]=1[CH3:21])=[O:15])[CH2:10]2
Reactant: C1COCCO1
Reactant: Cc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Product: Cc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1-c1ccc(C(=O)O)cc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 42 %

Procedure:
A solution of 1M sodium hydroxide (24.28 mL, 24.28 mmol) was added to a stirred suspension of N-(2-adamantyl)-1-(4-cyanophenyl)-5-methyl-pyrazole-4-carboxamide (Intermediate #66) (1.25 g, 3.47 mmol) in dioxane (25 mL). The resulting suspension was stirred at 100° C. for 7 hours. The reaction mixture was concentrated, diluted with water (40 mL) and filtered through Celite. The filtrates were acidified with 1M citric acid. The to precipitate was recovered by filtration, washed with water (3×20 mL) and dried under vacuum at 50° C. The crude product was purified by preparative HPLC (Phenomenex Gemini C18 110A (axia) column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 4-[4-(2-adamantylcarbamoyl)-5-methyl-pyrazol-1-yl]benzoic acid (550 mg, 42%) as a pale yellow powder.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=[C:15](OCC)[C:14]2=[O:26])=[CH:9][CH:8]=1>O>[NH2:5][C:15]1[C:14](=[O:26])[N:13]([C:10]2[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=2)[C:22]2[C:17]([N:16]=1)=[CH:18][CH:19]=[CH:20][CH:21]=2
Reactant: CCOc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Product: Nc1nc2ccccc2n(-c2ccc(Cl)cc2)c1=O
Yield: 70.4 %

Procedure:
To a melt of ammonium acetate (62 g) at 160° C. was added 1-(4-chlorophenyl)-1,2-dihydro-3-ethoxyquinoxalin-2-one (8.8 g) and the temperature was then raised during 5 minutes to 200° C. and maintained at this level for 15 minutes. The melt was cooled, water was added, and the product was filtered off. Crystallisation from ethanol gave the title compound (5.6 g) mp 254°-255° C.
Reaction SMILES: [NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([NH:26][C:27](=O)[O:28]CC)=[C:18]([F:32])[CH:17]=1.C(O)(=O)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:18]([F:32])[CH:17]=1
Reactant: CCOC(=O)/C=C(\N)C(F)(F)F
Reactant: CCOC(=O)Nc1cc(OC(C)C)c(Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
A solution of 10.5 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 25 ml of absolute dimethylformamide is added dropwise while stirring at 0° C. during 5 minutes to a suspension of 2.5 g of a 55% sodium hydride dispersion in 25 ml of absolute dimethylformamide. The temperature rises to 20° C. and the mixture is subsequently stirred at this temperature for 30 minutes. Thereafter, 14.4 g of ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate are added, and the mixture is stirred at room temperature for 30 minutes and heated at 150° C. (bath temperature) for 2.5 hours. The reaction mixture is cooled to 50° C., neutralized with 3.5 ml of concentrated acetic acid and largely concentrated at 60° C. under reduced pressure. The residue is poured into a solution of 200 ml of water and 30 ml of 2N hydrochloric acid and the aqueous mixture is extracted twice with 150 ml of diethyl ether each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether-n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].Cl[C:39]1[CH:44]=[C:43]([O:45][CH3:46])[N:42]=[C:41]([O:47][CH3:48])[N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][C:39]3[CH:44]=[C:43]([O:45][CH3:46])[N:42]=[C:41]([O:47][CH3:48])[N:40]=3)[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Product: COc1cc(Oc2cc3c(cc2OC)CCN(CC(=O)NC2CCc4ccccc42)C3Cc2ccc(OC)c(OC)c2)nc(OC)n1

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with 4-chloro-2,6-dimethoxy-pyrimidine
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][NH:49][CH2:48]1.[NH:54]1[CH:58]=[C:57]([C:59](O)=[O:60])[CH:56]=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:52])[CH2:46][C@@H:47]1[CH2:51][CH2:50][N:49]([C:59]([C:57]2[CH:58]=[N:54][NH:55][CH:56]=2)=[O:60])[CH2:48]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: O=C(C[C@@H]1CCNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(C[C@@H]1CCN(C(=O)c2cn[nH]c2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-[(3S)-pyrrolidin-3-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-4-carboxylic acid as the starting materials in 66% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z=544.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1[O:15][CH3:16])CC.[Br:18][CH2:19][CH2:20][CH2:21]O.C[CH:24]([O:26]C(/N=N/C(OC(C)C)=O)=O)C.C1(C)C=CC=CC=1>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([O:26][CH3:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH2:20][CH2:19][Br:18])=[CH:10][C:9]=1[O:15][CH3:16]
Reactant: OCCCBr
Reactant: CCC(Cc1ccc(O)cc1OC)C(=O)OC
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(OCCCBr)cc1OC)OC

Procedure:
3-(4-Hydroxy-2-methoxy-phenyl)-2-methoxy-propionic acid methyl ester (Example 188, Step C) and 3-bromo-propan-1-ol (Step A) were treated in the standard Mitsunobu conditions B (DIAD/toluene) to afford the title compound. 1H-NMR (CDCl3, 200.15 MHz): δ 7.01 (d, 1H, J=8.3), 6.39 (m, 2H), 4.06 (t, 2H, J=5.9), 4.00–3.96 (m, 1H), 3.78 (s, 3H), 3.67 (s, 3H), 3.57 (t, 2H, J=6.4), 3.31 (s, 3H), 2.99 (dd, 1H, J=13.7, 6.2), 2.91 (dd, 1H, J=13.7, 7.5), 2.34–2.22 (m, 2H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1.[CH2:22]([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:22]([O:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH:2]2[CH2:7][CH2:6][CH:5]([O:8][C:9](=[O:11])[CH3:10])[CH2:4][CH:3]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)=[O:32])=[CH:34][CH:35]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2CC(OC(C)=O)CCC2N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCOc1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC)c2)cc1
Yield: 92.7 %

Procedure:
790 mg of (±)-acetic acid (1RS,3RS,4RS)-4-amino-3-(3,4-dimethoxyphenyl)cyclohexyl ester (compound B1), 620 mg of 4-butoxybenzoic acid, 614 mg of N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride and 2 mg of 4-dimethylaminopyridine are stirred in 7 ml of dichloromethane for 18 h. 5 ml of water are added, the phases are separated and once the organic layer is extracted with 3 ml of dichloromethane. Then the organic layer is washed with 2.5 ml of saturated aqueous potassium bicarbonate solution and the aqueous solution is once extracted with 5 ml of dichloromethane. The combined organic layers are dried over magnesium sulfate, then the solvent is removed to give 1172 mg of the title compound as a colorless foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[O:14][C:8]1([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH2:7][C:6]2=[O:18].[C:19]([O:24][C@@H:25]([C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(O)(C)C>[C:19]([O:24][C@@H:25]([C:27]1[N:28]=[C:29]([N:11]2[CH2:12][CH2:13][C:8]3([CH2:7][C:6](=[O:18])[C:5]4[C:15](=[CH:16][CH:17]=[C:3]([Cl:2])[CH:4]=4)[O:14]3)[CH2:9][CH2:10]2)[CH:30]=[CH:31][N:32]=1)[CH3:26])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: O=C1CC2(CCNCC2)Oc2ccc(Cl)cc21
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Yield: 100 %

Procedure:
To a solution of 6-chloro-spiro[chroman-2,4′-piperidin]-4-one hydrochloride (prepared according to the method of Example 78, Step A, 175 mg, 0.61 mmol) in isopropanol (5 mL) was added (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 160 mg, 0.70 mmol) followed by triethylamine (0.29 mL, 2.1 mmol). This mixture was stirred at reflux for 1.5 h, concentrated, and purified by flash column chromatography (1% methanol/chloroform) to give 270 mg (100%) of the title compound of Example 78, Step B as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.19 (d, 1H), 7.83 (d, 1H), 7.44 (dd, 1H), 6.97 (d, 1H), 6.37 (d, 1H), 5.64 (q, 1H), 4.18 (app s, 2H), 3.34 (t, 2H), 2.72 (s, 2H), 2.37 (t, 2H), 2.10 (d, 2H), 1.71-1.60 (c, 4H), 1.55 (d, 3H), 0.94 (t, 3H); MS (APCI) 444, 446 (MH+).
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([C:10]2[C:22]3[C:21]4[CH:20]=[C:19]([O:23][CH3:24])[C:18]([O:25][CH3:26])=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[OH-].[K+].[CH:37](B1OC(C)(C)C(C)(C)O1)=[CH2:38]>CN(C)C=O.O.COCCOC>[CH3:26][O:25][C:18]1[C:19]([O:23][CH3:24])=[CH:20][C:21]2[C:22]3[C:10]([C:8]4[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH:37]=[CH2:38])[CH:9]=4)=[N:11][NH:12][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)c(Br)c4)c3c2cc1OC
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: COCCOC
Product: C=Cc1cc(-c2n[nH]c3cnc4cc(OC)c(OC)cc4c23)ccc1C#N
Temperature: 150 °C
Yield: 52.5 %

Procedure:
2-Bromo-4-(7,8-dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (540 mg, 1.32 mmol) is dissolved in N,N-dimethylformamide (4.0 ml) under an argon protective-gas atmosphere. Tripotassium phosphate (578 mg, 2.64 mmol), KOH (67 mg, 1.19 mmol), 1,2-dimethoxyethane (9.0 ml) and water (50 μl), vinylboronic acid pinacol ester (942 μl, 5.28 mmol) and trans-bis(tricyclohexylphosphine)palladium(II)dichloride (98 mg, 132 μmol) are subsequently added. The suspension obtained is heated at 150° C. (microwave) for 30 min. For work-up, the mixture is extracted with ethyl acetate and semi-saturated sodium chloride solution. The organic phase is dried over Na2SO4, filtered with suction and evaporated to dryness in vacuo. The residue is purified over flash silica gel (solvent gradient cyclohexane/0-80% by vol. of ethyl acetate), giving 4-(7,8-dimethoxy-3H-pyrazolo[3,4-c]-quinolin-1-yl)-2-vinylbenzonitrile (247 mg, 693 μmol) as a solid. MS: 357.2 (M+H+), TLC (HPTLC): Rf=0.47 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH:10]3[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(c1ccccc1)C(=O)N2
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Temperature: 60 °C
Yield: 60.3 %

Procedure:
A mixture of 5-(3,5-dimethylisoxazol-4-yl)-3-phenyl indolin-2-one (260 mg, 0.85 mmol), ethyl bromoacetate (172 mg, 1.0 mmol), potassium iodide (171 mg, 1.0 mmol) and potassium carbonate (260 mg, 1.88 mmol) in acetone (10 mL) was heated at 60° C. for 15 hours in a capped pressure tube. The mixture was then cooled to room temperature and diluted with ethyl acetate (30 mL) and extracted with water (2×30 mL) and brine (20 mL). Aqueous layers were back washed with ethyl acetate (30 mL). Organic layers were combined, dried (MgSO4), filtered and concentrated. Residue was purified by flash chromatography (dichloromethane, then 5% ethyl acetate in dichloromethane as solvent) to give product (200 mg, 59.9%). 1H NMR (400 MHz, DMSO-d6): δH 10.61 (s, 1H), 7.21-7.39 (m, 7H), 6.97 (d, J=8.0 Hz, 1H), 3.82-3.85 (m, 2H), 3.41 (s, 3H), 2.36 (s, 3H), 2.19 (s, 3H), 0.90 (t, J=6.8 Hz, 1H). MS (ESI) m/e [M+1]+ 391.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=3)=[CH:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.CN1CCCC1=O>O>[CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2)[CH:7]=[CH:8][C:9]=1[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1
Reactant: COc1ccc2ccc(-c3ccc4ccccc4c3)cc2c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Oc1ccc2ccc(-c3ccc4ccccc4c3)cc2c1
Temperature: 200 °C
Reaction time: 7 h

Procedure:
Under the nitrogen atmosphere, 7-methoxy-2,2′-binaphthalen (31.0) as the sixth intermediate compound, pyridine hydrochloride (63.0 g) and N-methylpyrrolidone (20 ml) were added to a flask and then stirred for 7 hours at 200° C. Once the heating is completed, it was cooled to 100° C. or less and added with water. The solid precipitated by adding water was collected by suction filtration. The obtained solid was purified by silica gel column chromatography (solvent: toluene) to give [2,2′-binaphthalen]-7-ol (22.0 g) as a seventh intermediate compound. The scheme is shown in the following “Reaction 12”.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:17])[S:11][C:12]=1[C:13]([O:15][CH3:16])=[O:14].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:10]1[S:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(C)nc1-c1ccccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)nc1-c1ccccc1Cl
Temperature: 25 °C

Procedure:
5.00 g (18.6 mmol) of methyl 4-(2-chlorophenyl)-2-methyl-1,3-thiazole-5-carboxylate and 3.38 g (19.0 mmol) of N-bromosuccinimide were dissolved in 100 ml of carbon tetrachloride and, with stirring, heated to the boil. At boiling point, 170 mg (1.00 mmol) of 2,2′-azobis-2-methylpropionitrile were added a little at a time over a period of 5 hours, followed by refluxing for a further hour. After cooling to room temperature, the reaction solution was filtered and the mother liquor was freed from the solvent under reduced pressure. The desired product was isolated by chromatographic purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](=[O:37])[O:29][C:28]=1[CH2:38]O.[Br:40]C(Br)(Br)Br.C(Cl)Cl>CO>[Br:40][CH2:38][C:28]1[O:29][C:30](=[O:37])[C:31]2[C:36]([C:27]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[F:20])=[CH:35][CH:34]=[CH:33][CH:32]=2
Reactant: BrC(Br)(Br)Br
Reactant: O=c1oc(CO)c(-c2ccccc2F)c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=c1oc(CBr)c(-c2ccccc2F)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Triphenylphosphine (0.127 g, 0.488 mmol)) was added to a solution of 4-(2-fluorophenyl)-3-(hydroxymethyl)-1H-isochromen-1-one (intermediate B4, 40 mg, 0.148 mmol) and perbromomethane (0.161 g, 0.488 mmol) in DCM (0.7 ml, 57.5 mmol), and the resulting mixture was stirred at RT for 24 hrs. The reaction was taken up with MeOH then concentrated under reduced pressure. The crude was purified over a Biotage Silica 10 g SNAP cartridge with a gradient of hexane and EtOAc to give the title compound (37 mg, 75%).