Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:15]=1.O1C2C=CC=CC=2N=C1C1C(N)=NC=C([Br:55])C=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:12][CH:13]=[C:14]([Br:55])[CH:15]=1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cc1-c1nc2ccccc2o1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)cc1-c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate used as starting material was prepared as follows: N,N-dimethylpyridin-4-amine (42.1 mg) was added to 3-(1,3-benzoxazol-2-yl)-5-bromo-pyridin-2-amine (500 mg) and di-tert-butyl dicarbonate (1.069 g) suspended in DMF (5 ml). The resulting mixture was stirred at 25° C. for 48 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate (15 ml). The resulting precipitate was collected by filtration, washed with water and dried. The crude was taken up into ethyl acetate and filtered through a pad of silica gel. The resulting filtrate was concentrated to afford tert-butyl N-[3-(1,3-benzoxazol-2-yl)-5-bromo-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (710 mg) as a solid. NMR Spectrum: (CDCl3): 1.32 (s, 18H), 7.37-7.44 (m, 2H), 7.60 (dd, 1H), 7.80 (dd, 1H), 8.70 (d, 1H), 8.81 (d, 1H); Mass spectrum: M+H+ 491;
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C@H:24]([CH2:26]OS(C3C(C)=CC=CC=3)(=O)=O)[CH2:23][C:22]=2[CH:38]=1>>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C@H:24]([CH2:26][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=4)([OH:13])[CH2:12][CH2:11]3)[CH2:23][C:22]=2[CH:38]=1
Reactant: OC1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: COc1ccc2c(c1)C[C@@H](COS(=O)(=O)c1ccccc1C)O2
Product: COc1ccc2c(c1)C[C@@H](CN1CCC(O)(Cc3ccc(Cl)cc3)CC1)O2

Procedure:
The title compound, MS: m/e=387.9 (M+H+), was prepared from 4-(4-chloro-benzyl)-piperidin-4-ol and (S)-toluenesulfonic acid 5-methoxy-2,3-dihydro-benzofuran-2-ylmethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:6]=[C:7]2[C:12]=1[O:11][CH:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2.[OH:31]O.[OH-].[Na+].Cl>C1COCC1.O>[OH:31][C:5]1[CH:6]=[C:7]2[C:12](=[C:3]([O:2][CH3:1])[CH:4]=1)[O:11][CH:10]([C:13]([F:14])([F:16])[F:15])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8]2
Reactant: CCOC(=O)C1=Cc2cc(B3OC(C)(C)C(C)(C)O3)cc(OC)c2OC1C(F)(F)F
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1=Cc2cc(O)cc(OC)c2OC1C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 424.6 %

Procedure:
The ethyl 8-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.21 g, 0.49 mmole) was dissolved in THF (3 mL) and cooled to 0° C. (ice bath). Hydrogen peroxide (0.25 g, 0.074 mmole) followed by 2.5N sodium hydroxide (0.20 mL) was added dropwise and the resulting solution was stirred for 3 hours. The contents were poured into water (20 mL) and acidified using 2.4 N HCl to pH around 1 and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to flash chromatography (silica gel) and eluted with 0-35% EtOAc/ hexanes to give yellow solid (0.1 g, 65%). LCMS m/z 319.0 (M+H). 1H NMR (CDCl3/400 MHz) 7.58 (s, 1H), 6.50 (s, 1H), 6.29 (s, 1H), 5.66 (q, 1H, J=7.0 Hz), 4.29 (m, 2H), 3.86 (s, 3H), 1.32 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:17])=[CH:6][CH:5]=[CH:4][C:3]=1[C:18]1[C:30]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][C:22]=2[C:21]([C:31]([NH2:33])=[O:32])=[CH:20][CH:19]=1.Cl.[OH-:35].[Na+]>C1COCC1>[OH:35][CH:21]([CH2:31][OH:32])[CH2:22][NH:23][C:26]1[CH:25]=[C:24]2[C:29]([C:30]3[C:18]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([N:8]5[CH2:16][C:15]6[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=6)[C:9]5=[O:17])[C:2]=4[CH3:1])=[CH:19][CH:20]=[C:21]([C:31]([NH2:33])=[O:32])[C:22]=3[NH:23]2)=[CH:28][CH:27]=1
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4ccccc4c23)cccc1N1Cc2ccccc2C1=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(NCC(O)CO)ccc4c23)cccc1N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 74(S)-2,2-dimethyl-1,3-dioxolan-4-yl)methylamino)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide (Example 66-15, 50 mg, 0.089 mmol) in THF (1 mL) was treated with 2 M hydrochloric acid (4.46 mL, 8.92 mmol) and the mixture was stirred at rt for 1 h. The mixture was made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The combined organic phases, along with some insoluble precipitate, were dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from DCM to 90:9:1 DCM-methanol-28% aqueous ammonium hydroxide) to provide 7-(2,3-dihydroxypropylamino)-4-(2-methyl-3-(1-oxoisoindolin-2-yl)phenyl)-9H-carbazole-1-carboxamide as an orange solid (20 mg, 39%). 1H NMR (400 MHz, methanol-d4) δ 7.90 (1 H, d, J=7.49 Hz), 7.79 (1 H, d, J=7.77 Hz), 7.67-7.74 (2 H, m), 7.58-7.62 (1 H, m), 7.49-7.55 (2 H, m), 7.42 (1 H, dd, J=6.94, 1.94 Hz), 6.99 (1H, d, J=7.77 Hz), 6.86 (1 H, d, J=8.32 Hz), 6.81 (1 H, d, J=1.94 Hz), 6.45 (1 H, dd, J=8.74, 1.80 Hz), 4.97 (2 H, s), 3.88-3.93 (1 H, m), 3.59-3.68 (2 H, m), 3.36-3.39 (1 H, m), 3.14-3.20 (1 H, m), 1.95 (3 H, s). Mass spectrum m/z 521.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]=2[C:21]=1[CH3:22].Cl[C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][N:28]2[CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:6]=2[C:21]=1[CH3:22]
Reactant: COC[C@H](N)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C)c2n1-c1ccccc1
Temperature: 90 °C

Procedure:
A mixture of (R)-1-(6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (270 mg, 0.9 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (258 mg, 1.08 mmol) and DIPEA (308 μL, 1.8 mmol) in n-butanol (5 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford [(R)-1-(6-fluoro-7-methyl-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine: LCMS (Method C): RT 3.38 min [M+H]+ 502.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2.[C@@H:19]12[CH2:25][C@@H:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[C@@H:19]12[CH2:25][C@@H:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[CH:6]=[CH:5]2
Reactant: OC1C[C@@H]2CC[C@H]1C2
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@]1(c2ccc3cc(OC4C[C@@H]5CC[C@H]4C5)ccc3c2)COC(=O)N1
Yield: 40 %

Procedure:
The compound was prepared in a manner similar as to that described above (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one, (1S,4R)-Bicyclo[2.2.1]heptan-2-ol (1.0 g, 0.0090 mol), triphenylphosphine (2.6 g, 0.0099 mol), h (45 mL, 0.55 mol), and diisopropyl azodicarboxylate (2.0 g, 0.0099 mol) to give 502 mg of the desired product as a white solid (40%). 1H NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 2H), 4.67 (br. s., 2H), 4.33-4.17 (m, 1H), 3.84-3.51 (m, 2H), 2.49-0.78 (m, 11H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH2:14])[O:9][C:8]=2[CH:15]=1.Br[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:31])[CH:26]=[CH:27][O:28]2)=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:30]=[C:29]4[C:24]([C:25](=[O:31])[CH:26]=[CH:27][O:28]4)=[CH:23][CH:22]=3)[O:9][C:8]=2[CH:15]=1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: O=c1ccoc2cc(OCCCBr)ccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCOc1ccc3c(=O)ccoc3c1)CO2
Temperature: 80 °C
Yield: 4.4 %

Procedure:
2,3-Dihydro-7-methoxy-1,4-benzodioxin-2-methanamine hydrochloride (4.0 g, 17 mmole), 7-(3-bromopropoxy)chromen-4-one (4.9 g, 17 mmole) and diisopropylethylamine (15.1 ml, 87 mmole) were combined in 150 ml of DMF and heated at 80° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuum. The residue was chromatographed on a silica gel column using first dichloromethane and then 5% methanolic dichloromethane as eluents. The fractions containing material with Rf=0.59 on silica gel tlc (chloroform/methanol/ammonia=95/5/1) were combined, concentrated, and the residue was dissolved in 50% methanol/dichloromethane. The mixture was then treated with 4N isopropanolic HCl until the solution was 3 in pH and crystallized by triturating with ether. Two further recrystallizations gave 0.3 g of title compound as a yellow solid hydrochloride, quarter hydrate, m.p. 155°-157° C.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Cl[CH2:15][C:16]#[N:17].O>CN(C=O)C>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[CH2:15][C:16]#[N:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCN1C(=O)c2ccccc2C1=O
Yield: 89.4 %

Procedure:
32 g (0.217 mol) of isoindole-1,3-dione in 160 mL of DMF were treated with 11.75 g (0.294 mol, 1.35 eq) of NaH (60% in oil) over 45 min at 0° C. 22.17 g (0.294 mol, 1.35 eq) of chloro-acetonitrile were added, and the reaction was stirred over night. The reaction mixture was poured into 1.5 L of water, and the precipitate was collected by filtration, washed with Et2O and dried under high vacuum to afford 36.1 g (89%) of (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetonitrile as a white solid, MS: 187 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]([CH3:29])[NH:26][CH:25]([CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH:27]([CH3:29])[N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH3:30])[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)N1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3,5-Dimethyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 417.
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([O:18]CC)=O)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[NH3:23]>>[CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16]([NH2:23])=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: N
Product: Cc1ccc2c(c1)c1c(n2CCC(N)=O)CCN(C)C1
Reaction time: 0.08 h

Procedure:
Ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (0.1 g, 0.33 mmol) was taken in 4 ml aqueous ammonia and heated at 120 deg C. for 5 min using in microwave. The solid product precipitated out after the reaction was filtered through a Buchner funnel and washed with 10% sodium bicarbonate (10 ml×2) followed by demineralised water (10 ml×2) wash to obtain 1.25 mg of 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) TFA SALT 9.85 (bs, 1H), 7.4-7.45 (m, 2H), 7.2 (s, 1H), 7.0 (d, 1H), 6.85 (s, 1H), 4.3-4.2 (m, 3H), 3.6-3.4 (m, 2H), 3.2-3.1 (m, 2H), 3.0 (s, 3H), 2.7 (m, 2H), 2.3 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12]Cl.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][N:18]1[C:14](=[O:24])[C:15]2[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17]1=[O:19]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1cc(Br)c(CCl)cc1OC
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1OC
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
A solution of 1-bromo-2-chloromethyl-4,5-dimethoxy-benzene (26.01 g, 0.09796 mol) in dry DMF (100 mL) was treated with potassium phthalimide (19.05 g, 0.1029 mol). The resulting slurry was heated to 80° C. while stirring under nitrogen for 4.5 h. The resulting mixture was then cooled to room temperature and allowed to stir 16 h. The resulting mixture solidified, was diluted with water (400 mL) and stirred 1 h. The resulting white precipitate was collected via filtration and washed with water (1 L). The white solid was dissolved in boiling methanol (2 L). The resulting solution was reduced to about 1 L, at which time a precipitate began to form. The resulting slurry was allowed to cool to room temperature then placed on an ice bath. The precipitate was collected via filtration to yield 2-(2-bromo-4,5-dimethoxy-benzyl)-isoindole-1,3-dione as a white solid.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:8][C:9]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>C1COCC1>[C:9]([Si:12]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:8]
Reactant: C=CCCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: C=CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.5 %

Procedure:
To a solution of 5-hexen-1-ol (5 g, 50 mmol) in THF (80 mL) were sequentially added TBDMSCl (8.4 g, 55 mmol) and imidazole (4.01 g, 60 mmol). The mixture was stirred at rt overnight. Water was added and the two phases separated. The aq. phase was extracted with ether and the combined org. layers were dried over MgSO4 and concentrated to give the title intermediate as a colourless liquid (11.2 g, 100% yield).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1.[Cu][C:21]#[N:22].NCCN>CN(C)C=O>[C:21]([C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])([C:9]([F:12])([F:11])[F:10])[O:8][C:4]=2[CH:3]=1)#[N:22]
Reactant: FC(F)(F)CC1(C(F)(F)F)Oc2ccc(Br)cc2O1
Reactant: N#C[Cu]
Solvent: NCCN
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Temperature: 160 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
35 g of the product of Example 24 were dissolved in 75 ml of dimethylformamide, and 10.5 g of copper(I) cyanide were added. The mixture was stirred for 8 hours at 160° C. The hot mixture was then discharged into 100 ml of ice-water, and 30 g of 1,2-diaminoethane were added. After stirring for 30 minutes, the organic phase was separated off and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with a solution of 30 g of 1,2-diaminoethane in 75 ml of water, dried over magnesium sulphate and distilled under high vacuum to give 20.5 g of product (=69% of theory). The. boiling point was 110° C. at 0.02 mbar. =19F NMR: -58.1 and -84.6 ppm. 1H NMR: 3.08 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([CH3:20])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:9]=1)[CH3:6])C.Cl.[H][H]>CO.[Pt]>[CH3:1][O:3][C:4](=[O:21])[C:5]([CH3:6])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]2[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH:9]=1)[CH3:20]
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(-c2cccnc2)c1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: COC(=O)C(C)(C)Oc1cccc(C2CCCNC2)c1
Yield: 82.3 %

Procedure:
2-methyl-2-(3-pyridin-3-yl-phenoxy)-propionic acid ethyl ester (6.0 g, 21.03 mmol) was dissolved in methanol (70 mL) and followed by the addition of 37% HCl (5.3 mL) and 10% Pt/C (0.60 g). The mixture was shaken with hydrogen under 50 psi at 50° C. in a Parr bottle for 5 h, filtered through a pad of Celite, and rinsed with methanol. GC/MS showed complete hydrogenation and only 50% of methyl ester conversion. Concentrated H2SO4 (2.0 mL) was added to the filtrate and the resulting solution was allowed to reflux under nitrogen overnight. After removal of excess methanol, the residue was treated with saturated Na2CO3 (150 mL) and extracted with ethyl acetate (2×200 mL). The organic extract was washed with water, dried over sodium sulfate, and concentrated to give 4.80 g (82%) of 2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid methyl ester as a yellow oil: 1H NMR (CDCl3) δ 1.59 (s, 6H), 1.78 (br, 1H), 1.97 (br d, 1H), 2.02 (br, 2H), 2.61 (m, 3H), 3.06 –3.13 (m, 2H), 3.76 (s, 3H), 6.61 (dd, 1H), 6.70 (s, 1H), 6.83 (d, 1H), 7.14 (t, 1H); MS m/z (relative intensity) 277 (M+, 2), 218 (6), 176 (100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C(Cl)CCl.[Cu]Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][C:14]2[N:15]([CH3:19])[C:16]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:18]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: Cn1cccc1CCNS(=O)(=O)c1ccc(F)cc1
Agent: Cl[Cu]
Solvent: ClCCCl
Product: CCOC(=O)Cc1ccc(CCNS(=O)(=O)c2ccc(F)cc2)n1C
Reaction time: 0.33 h

Procedure:
1.69 g of 2-(2-(4-fluorobenzenesulphonylamino)-ethyl)-1-methylpyrrol are dissolved in 6 ml of ethylene chloride and 0.06 g of copper(I)chloride are added. Under a nitrogen atmosphere the mixture is refluxed and then a solution of 0.34 g of ethyl diazoacetate in 6 ml of ethylene chloride is slowly added dropwise. After 20 minutes the evolution of nitrogen has ended and the suspension is concentrated to dryness by rotary evaporation. Then the residue is chromatographed over a silica gel column (ethylene chloride/ethyl acetate=100/1).
Reaction SMILES: [N:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[C:10]([CH2:20][CH3:21])=[N:11][N:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[CH2:28][CH3:29])[CH3:25]>C(#N)C.CCOC(C)=O.[Cu]I>[CH2:24]([O:26][CH:27]([O:30][CH2:31][CH3:32])[C:28]1[N:3]=[N:2][N:1]([C:4]2[CH:23]=[CH:22][C:7]([CH2:8][C:9]3[C:10]([CH2:20][CH3:21])=[N:11][N:12]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=34)=[CH:6][CH:5]=2)[CH:29]=1)[CH3:25]
Reactant: CCOC(CC)OCC
Reactant: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(N=[N+]=[N-])cc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(OCC)c1cn(-c2ccc(Cc3c(CC)nn4c(C)cc(C)nc34)cc2)nn1

Procedure:
A solution of 3-(4-azido-benzyl)-2-ethyl-5,7-dimethyl-pyrazolo[1,5-a]pyrimidine (20) (2 g, 6.53 mmol), propionaldehyde diethylacetal (1.294 g, 9.79 mmol) and copper(I) iodide (1.492 g, 7.83 mmol) in 33 ml of acetonitrile was stirred at r.t. for 24 h. The reaction was diluted in EtOAc and washed with sat aq Na2 CO3, water and brine. The organic layer was dried over anhydrous Na2 SO4, filtered and concentrated under HV. The crude product was purified by flash chromatography (silica gel, EtOAc/DCM 0% to 50%) to give a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](F)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]([O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)([CH3:20])[CH3:19].CC([O-])(C)C.[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:26][C:25]3[CH:24]=[CH:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:28][CH:27]=3)=[C:11]([C:16]#[N:17])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: N#Cc1cc(-c2ccc(Cl)c(Cl)c2)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Nc2ccc(-c3ccc(Cl)c(Cl)c3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3′,4′-dichloro-4-fluorobiphenyl-3-carbonitrile (173 mg, 0.650 mmol), 4-isopropoxyaniline (108 mg, 0.715 mmol), and KOtBu (154 mg, 1.375 mmol) in DMSO (4 mL) was stirred at rt for 1.5 h, The mixture was diluted with ethyl acetate, washed with H2O and brine, and then dried over Na2SO4. The solvent was removed and the product was purified by silica gel chromatography (eluting with hexane containing 0 to 8% ethyl acetate) followed by preparative HPLC (100×30 mm Luna C18 column, flow rate 42 ml permin, gradient elution starting with A:B=50:50 and ending with A:B=0:100 [A=10 mM NH4OAc in 5% aqueous acetonitrile; B=10 mM NH4OAc in 95% aqueous acetonitrile] over 20 min). This afforded 99 mg of 3′,4′-dichloro-4-(4-isopropoxyphenylamino)-biphenyl-3-carbonitrile which still contained some impurities according to the LC/MS but was used as such for next step. MS (ESI) m/z 397.1 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:8].[N+:16]([O-])([OH:18])=[O:17]>>[CH3:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)=[O:8]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To 15 mL of concentrated sulfuric acid at 0° C. is added 6.9 g (0.05 mmol) of 4-fluoroacetophenone. To the resulting solution is rapidly added a mixture of 4 mL nitric acid and 6 mL concentrated sulfuric acid. The reaction mixture is stirred at 0-5° C. for 3 hours. The reaction mixture is then poured into ice water, and the resulting mixture is extracted with chloroform. The combined organic fractions are washed with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue is purified using column chromatography on silica gel, eluting with 20% ethyl acetate/hexanes, yielding 6.0 g of 4-fluoro-3-nitroacetophenone (60% yield).