Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:20]1([C:24]([C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 8) (530 mg, 2 mmol), azetidin-1-yl-(5-bromopyridin-2-yl)methanone (CAS no. 845306-16-3) (531 mg, 2.2 mmol), caesium carbonate (1.956 g, 6 mmol) and tris(triphenylphosphine)copper bromide (CAS no. 15709-74-7) (373 mg, 0.4 mmol) in DMA (5 mL) was stirred at 160° C. for 6 hours. The DMA was evaporated under reduced pressure and the residue was dissolved in water (520 mL) washed with ethyl acetate (3×20 mL). The aqueous fraction was acidified with 2N hydrochloric acid and extracted with ethyl acetate (3×100 mL), the combined organic layers were washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in THF (6 mL) and methanol (3 mL) and was treated dropwise with 2M (trimethylsilyl)diazomethane in hexane (1.1 mL). The reaction was stirred for 30 min then treated with 1 drop of acetic acid, stirred for another 15 minutes and evaporated to dryness under reduced pressure. The residue was purified by chromatography eluting with 0-100% ethyl acetate/hexane to give afford the product (439 mg, 52%). 1H NMR δ (300 MHz, CDCl3) 2.10-2.24 (m, 1H), 2.35 (quintet, 2H), 2.52-2.67 (m, 1H), 2.93 (s, 3H), 3.34-3.56 (m, 2H), 3.89 (s, 3H), 4.25 (t, 2H), 4.70 (t, 2H), 4.91 (t, 1H), 6.99 (s, 1H), 7.32 (s, 1H), 7.35 (d, 1H), 7.53 (s, 1H), 8.10 (d, 1H), 8.31 (s, 1H); m/z 426 (M+H)+.
Reaction SMILES: N1C=CC=[C:3]([NH:7][C:8](=[S:30])[O:9][CH2:10]/[CH:11]=[C:12](\[CH3:29])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:28])/[CH2:17][CH2:18]/[CH:19]=[C:20](\[CH3:27])/[CH2:21]CC=C(C)C)C=1.C(O)/C=C(/CC/C=C(/CCC=C(C)C)\C)\C.CSN=C=O>>[CH3:3][NH:7][C:8](=[S:30])[O:9][CH2:10]/[CH:11]=[C:12](\[CH3:29])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:28])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:21])[CH3:27]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COC(=S)Nc1cccnc1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: CSN=C=O
Product: CNC(=S)OC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Yield: 47 %

Procedure:
Similar to the preparation of 38a, the reaction of alcohol 5 with methyl thioisocyanate afforded the desired compound 43 in 47% yield (316 mg) as a viscous oil as a mixture of isomers: TLC Rf: 38 (10% EtOAc/hexanes): 1H NMR (300 MHz, CDCl3): δ 6.5 (br s, 0.3H), 6.2 (br s, 0.7H), 5.40-5.39 (m, 1H), 5.09-5.08 (m, 2H), 5.03-5.01 (d, 0.7H), 4.97-4.94 (d, 1.3H), 3.09-3.08 (d, 2H), 2.88-2.86 (d, 1H), 2.12-1.96 (m, 8H), 1.73-1.72 (m, 3H), 1.68 (m, 3H), 1.60 (m, 6H). 13CNMR (75 MHz, CDCl3): δ 143.1, 135.7, 131.6, 124.5, 123.8, 118.9, 118.2, 69.2, 67.6, 39.9, 39.8, 21.1, 30.0, 26.9, 26.4, 26.0, 18.0, 17.0, 16.9, 16.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:20][CH:19]2[N:5]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=32)[CH2:4][CH2:3]1.[N:21]#CBr.O>C1C=CC=CC=1.C(OCC)C>[C:1]([N:2]1[CH2:3][CH2:4][N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[CH:19]2[CH2:20]1)#[N:21]
Reactant: CN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: N#CBr
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: N#CN1CCN2c3ccccc3Cc3ccccc3C2C1
Reaction time: 24 h

Procedure:
A solution of mianserin (5.2 g) in anhydrous benzene (20 ml) was added slowly to a stirred solution of cyanogen bromide (2.3 g) in anhydrous benzene (20 ml) in an atmosphere of nitrogen. After 24 hours, the mixture was diluted with diethyl ether (50 ml) and shaken with water (50 ml). The separated aqueous layer was back extracted with a mixture of benzene and ether (equal volumes of each, total 50 ml) and the combined organic layers dried over anhydrous potassium carbonate and then evaporated under reduced pressure. The residual solid was recrystallised from ethanol to give 2-cyanonormianserin as colourless needles m.p. 164°-166° C. This compound is outside general formula I, and was used as an intermediate only.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc(N)c2ncccc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c2ncccc12
Yield: 54.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-methylquinolin-8-amine (Intermediate 44) (690 mg, 4.38 mmol) and 2-nitrobenzenesulfonyl chloride (1.15 g, 5.24 mmol) gave the title compound (820 mg, 57%). The structure was confirmed by 1H NMR.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:3]=1.[CH2:41]([N:49]1[CH:53]=[C:52](B2OC(C)(C)C(C)(C)O2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:41]([N:49]1[CH:53]=[C:52]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[C:13]([NH:17][CH:18]5[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]5)[CH:14]=[CH:15][CH:16]=4)[CH:9]=3)[N:4]([S:31]([C:34]3[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=3)(=[O:33])=[O:32])[CH:3]=2)[CH:51]=[N:50]1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC1(C)OB(c2cnn(CCc3ccccc3)c2)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4cccc(NC5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc32)cc1
Yield: 70.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, tert-butyl 4-((3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)amino)piperidine-1-carboxylate (intermediate 66E) (200 mg, 0.297 mmol) was coupled with 1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 59) (133 mg, 0.446 mmol) using Pd(PPh3)2Cl2 (11 mg, 0.014 mmol) and sodium carbonate (79 mg, 0.744 mmol) in toluene/ethanol/water (5/2/1 ml) to afford 150 mg (70.4% yield) of the titled compound after column purification using 1% methanol in DCM as eluent. MS: m/z=717.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22]C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=[O:22]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCOCC1
Temperature: 100 °C
Yield: 99.8 %

Procedure:
A mixture of 6-methoxy-7-(2-morpholinoethoxy)-4-phenoxyquinazoline (400 mg, 1.05 mmol) and 2M hydrochloric acid (10 ml) was heated at 100° C. for 2 hours and then allowed to cool. The mixture was neutralised with solid sodium hydrogen carbonate. Addition of methylene chloride gave a white precipitate which was collected by filtration, washed with acetone and dried to give 6-methoxy-7-(2-morpholinoethoxy)-3,4-dihydroquinazolin-4-one (320 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[NH:24]([C:29]([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:25][C:26]([OH:28])=O.C[N:47]([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(=O)([O-])O.[Na+]>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]\[C:12]2[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:29]([NH:24][CH2:25][C:26]([NH2:47])=[O:28])([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 60 °C

Procedure:
Two grams (6.3 mmols) of (Z)-1-(3-amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-ethene, 2.3 g of Fmoc-Gly and 11 g (25 mmols) of a BOP reagent were dissolved in 40 ml of N,N-dimethylformamide, and the mixture was heated at 60° C. for 2 hours. After the reaction mixture was cooled, a saturated aqueous solution of sodium hydrogencarbonate was added thereto. The resulting mixture was extracted three times with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The product was purified through silica-gel column chromatography (mixture of ethyl acetate and hexane at a ratio by volume of 1:2) to give 1.63 of the final product in a yield of 43.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:22])[CH:16]=[CH:15][C:14]=2[CH:20]=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2C=O)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccccc1-c1ccc(C=O)c(OC2CN(C(=O)OC(C)(C)C)C2)c1
Yield: 99.1 %

Procedure:
To 3-(5-Bromo-2-formyl-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (1.4 g, 3.9 mmol), 2-methylphenylboronic acid (0.55 g, 4.1 mmol), K3PO4 (2.5 g, 11.7 mmol), Pd(dba)2 (0.046 g, 0.080 mmol) and QPhos (0.114 g, 0.160 mmol) was added PhCH3 (16 mL). After 18 h at rt the reaction was diluted with EtOAc and filtered through a small silica pad. Silica gel chromatography (10-40% EtOAc in hexanes) gave 1.42 g (98% yield) of the title compound. 1H NMR (CDCl3): 7.26-7.18 (m, 4H), 6.94 (d, J=8.3 Hz, 1H), 6.90 (dd, J=8.2, 2.0 Hz, 1H), 6.55 (d, J=1.9 Hz, 1H), 4.90-4.86 (m, 1H), 4.26 (dd, J=10.1, 6.3 Hz, 2H), 4.12 (m, 4H), 2.26 (s, 3H), 1.49 (t, J=7.0 Hz, 3H), 1.44 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH:4]([OH:15])[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>C(#N)C>[Br:14][C:8]1[CH:7]=[C:6]([CH2:5][CH:4]([OH:15])[C:3]([OH:2])=[O:16])[CH:11]=[C:10]([Br:12])[C:9]=1[O:13][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)C(O)Cc1cc(Br)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)C(O)Cc1cc(Br)c(OCc2ccc3ccccc3c2)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(3,5-dibromo-4-hydroxyphenyl)-2-hydroxypropionic acid methyl ester (0.25 mmol) and potassium carbonate (0.3 mmol) in acetonitrile (5 mL) was stirred for 10 minutes at room temperature under nitrogen. 2-Bromomethylnaphthalene (0.3 mmol) dissolved in acetonitrile (1 mL) was added with a syringe. The reaction mixture was stirred for 15 hours at room temperature under nitrogen. After concentration in vacuo, the light yellow residue was diluted with ethyl acetate (20 mL) and washed with brine (25 mL). The organic phase was dried over magnesium sulphate and concentrated in vacuo. The residue was purified on column (ethyl acetate/n-heptane 1:3). The fractions containing the coupled material were pooled, concentrated and dissolved in methanol (10 mL), and an aqueous solution of lithium hydroxide (10 mL, 1N) was added carefully. The reaction mixture was stirred for 15 hours at room temperature, acidified with hydrochloric acid (2 N) and the volatile solvents removed in vacuo. The formed precipitate was collected, washed with water and purified with HPLC (YMC-Pack, D-C8-5, 250×20 mm, 5 μm, 120A; Mobile phase: 40% acetonitrile and 60% 25 mM ammonium acetate). This gave 11 mg (9%) of 3-[3,5-dibromo-4-(naphthalen-2-ylmethoxy)phenyl]-2-hydroxypropionic acid as a white solid mass. LC/MS (electrospray): m/z 479 (M−1).
Reaction SMILES: C(OC([C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1)=O)C.[CH3:34][O:35]C1C=CC(B(O)O)=CN=1>>[CH3:34][O:35][C:6]1[CH:33]=[CH:32][C:9]2[N:10]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:17][CH:18]=3)[S:12][C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)sc2c1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1

Procedure:
The title compound was prepared according to the method used for the preparation of 2-[6-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]-3-pyridinyl]-6-benzothiazolecarboxylic acid ethyl ester, from 2-methoxy-5-pyridineboronic acid (0.48 g, 3.14 mmol), and obtained as a solid (0.29 g) after purification by flash column chromatography using 15% ethyl acetate in hexane. 1H NMR δ 8.94 (d, 1H) 8.81 (s, 1H) 8.40 (dd, 1H) 8.00-8.19 (m, 2H) 7.04 (d, 1H) 4.37 (q, 2H) 3.97 (s, 3H) 1.36 (t, 3H); MS m/z (M+H) 315.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH:6]=1.CO[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1>C1COCC1>[O:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([B:18]2[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]2)[CH:3]=[N:4]1
Reactant: Ic1cnn(CCOC2CCCCO2)c1
Reactant: COB1OC(C)(C)C(C)(C)O1
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
This stage was prepared like described in patent application US 2007/0265272, p. 38 & 39: To a solution of 4-iodo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazole (Stage 171.5, 7 g, 21.73 mmol) in anhydrous THF (55 mL) was added at 0° C. under argon iPrMgCl in THF (2 M, 21.73 mL) drop by drop. The RM was stirred at 0° C. for 1 h. Then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.36 g, 32.6 mmol) was added at 0° C. and the solution was stirred at rt for 1 further hour. The RM was then quenched with 140 mL sat. aqueous NH4Cl and extracted with 3×150 mL EtOAc. The combined organic layers were washed with 70 mL sat. aqueous NH4Cl, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography (4×20 cm, Hexane/EtOAc 5%-40%) to afford the title compound as a colorless oil (tR 3.20 min (conditions 8), MH+=323).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]([CH3:22])([CH3:21])[CH2:9][C:10]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[CH2:11][OH:12])[CH:7]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]([CH3:21])([CH3:22])[CH2:9][C:10]([O:17][CH2:18][O:19][CH3:20])([C:13]([F:16])([F:15])[F:14])[CH:11]=[O:12])[CH:7]=1
Reactant: COCOC(CO)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COCOC(C=O)(CC(C)(C)c1cc(F)ccc1OC)C(F)(F)F
Reaction time: 72 h
Yield: 92.9 %

Procedure:
To a solution of 2.77 g (7.82 mmol) of the above 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentan-1-ol in 50 mL of dichloromethane was added 3.8 g (17.63 mmol) of pyridinium chlorochromate. After 3 days, the reaction was diluted with 100 mL of hexanes and filtered through a pad of silica gel in a 150 mL funnel, eluting with EtOAc-hexanes (1:9). Concentration in vacuo afforded 2.56 g (93%) of 4-(5-fluoro-2-methoxyphenyl)-2-methoxymethoxy-4-methyl-2-trifluoromethylpentanal as a clear oil which was used without further purification.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)O1.[Cl:29][C:30]1[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[N:31]=[CH:32][N:33]=[C:34]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:10]=2)[CH:35]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(Cl)ncn3)c3cccnc32)cc1
Yield: 33 %

Procedure:
A solution of boronate 4 (0.11 g, 0.276 mmol), 4,6-dichloropyrimidine (0.049 g, 0.331 mmol), catalytic Pd(PPh3)4 and excess potassium carbonate in DMF was heated in the microwave at 160° C. for 5 minutes resulting in conversion to product by TLC (20% EtOAc:hexanes). The reaction was partitioned between EtOAc/H2O, extracted, stripped down in vacuo and purified by silica column (eluent:5% EtOAc:hexanes) giving 8 (0.035 g) as a white solid in 33% yield.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19](O)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.O1CCCC1.[F:37][C:38]([F:47])([F:46])[C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42]>CN(C)C=O.CN1CCCC1=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=4)[C:19]([NH:42][C:41]4[CH:43]=[CH:44][CH:45]=[C:39]([C:38]([F:37])([F:46])[F:47])[CH:40]=4)=[O:20])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 9 %

Procedure:
Using 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoic acid (100 mg, 0.30 mmol), oxalyl chloride (100 μL, 1.2 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), 3-(trifluoromethyl)aniline (80 mg, 0.48 mmol) and N-methylpyrrolidone (1.0 mL) as starting materials and in the same manner as in Example 335, the title compound (13 mg, 8.9%) was obtained as a pale-yellow powder.
Reaction SMILES: [CH:1]([N:4]([CH:27]([CH3:29])[CH3:28])[C:5](=O)[CH2:6][CH:7]([C:14]1[CH:15]([O:24]C)[C:16](=C=O)[CH:17]=[C:18](OC)[CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:39][CH2:38]C1.[Cl-].[Al+3].[Cl-].[Cl-]>O1CCCC1>[CH:27]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH2:38][OH:39])[CH:17]=[CH:16][C:15]=1[OH:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:28])[CH3:29]
Reactant: COC1=CC(=C=O)C(OC)C(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)=C1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: CC(C)N(CCC(c1ccccc1)c1cc(CO)ccc1O)C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (±)-N,N-diisopropyl-3-(2-methoxy-5-methoxy-carbonylphenyl)-3-phenylpropionamide (0.79 g, 2.0 mmol) in 20 ml of tetrahydrofuran was cooled to 5° C. and then treated with 2.5 ml of 1M LiAlH4/THF. After stirring at room temperature for 18 hrs. finely powdered aluminium chloride (0.3 g) was added and stirring was continued for additional 4 hrs. The reaction was quenched at 5° C. by the dropwise addition of water followed by aqueous sodium hydroxide solution. The mixture was diluted with diethyl ether (150 ml) and the organic phase was washed with half saturated brine, dried (sodium sulphate), and evaporated to dryness to give the title compound as a solid off-white foam. Tlc (2) 0.16, m.p. 48-51° C. A portion of the material was converted into the hydrochloride (ethereal hydrochloric acid), m.p. 186-189° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.Br[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:7]([CH2:8][CH3:9])[CH2:6][CH3:5])[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: O=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: O=C(Cl)CCCBr
Product: CCN(CC)CCCC(=O)N1c2ccc(Cl)cc2NC(=O)c2ccccc21

Procedure:
The 5-(5-bromobutyryl)-8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one, used as starting material, is synthesized similarly to the starting material described in Example 1 from 8-chloro-5,10-dihydro-11H-dibenzo(b,e)(1,4)-diazepine-11-one and 4-bromobutyryl chloride. The yield is 83.1% of the theoretical yield and the melting point is 176°-177° C.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([CH3:19])[CH3:18])[C:12]=1[NH2:20])([CH3:10])[CH3:9].[Cl:21][CH2:22][C:23](Cl)=[O:24]>ClCCl>[Cl:21][CH2:22][C:23]([NH:20][C:12]1[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]([CH3:19])[CH3:18])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
222 mL (1.59 mol) of triethylamine are added to a solution of 300 mL (1.59 mol) of 2,6-diisopropyl-phenylamine (Starting material 3) in 1 litre of dichloromethane. The reaction mixture is cooled to 0° C., and 127 mL (1.59 mol) of chloroacetyl chloride are then added dropwise. Once the addition is complete, the ice bath is removed and the medium is stirred for 20 minutes. It is then poured into water and extracted with dichloromethane. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The residue is filtered through silica gel (eluent: dichloromethane). The filtrate is evaporated and then triturated in heptane. 2-Chloro-N-(2,6-diisopropyl-phenyl)acetamide is obtained in the form of a white solid.