Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13](O)=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([Cl:21])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Solvent: c1ccccc1
Product: CC(C(=O)Cl)c1ccc(C(=O)c2cccs2)cc1

Procedure:
A mixture of 5.2 parts of p-(2-thenoyl)hydratropic acid, 4.8 parts of thionyl chloride and 32 parts of anhydrous benzene is stirred and refluxed for 3h. 30. The reaction mixture is evaporated and the residue is evaporated once more from benzene, yielding p-(2-thenoyl)hydratropoyl chloride as a residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])[CH2:19][C:18]2=[O:31])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:32])[CH2:16][N:17]2[CH:20]([S:21]([CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[O:41])[CH2:19][C:18]2=[O:31])=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOC(=O)CCCSC1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Product: C=CCOC(=O)CCCS(=O)C1CC(=O)N1CC(=O)NCCCCCCc1ccc(F)cc1
Yield: 21 %

Procedure:
Treatment of N-[6-(4-Fluorophenyl)hexyl]-[4-(3-allyloxycarbonylpropyl)thio-2-oxo-azetidin-1-yl]-acetamide with mCPBA as described for Example 17 gave thetitle compound as a white crystalline solid, m.p. 95-96° C., 21% yield
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH2:13][CH2:14][NH2:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>C(O)(=O)C>[Br:1][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[CH2:13][CH2:14][NH2:15]
Reactant: BrBr
Reactant: COc1ccc(CCN)cc1OC
Solvent: CC(=O)O
Product: COc1cc(Br)c(CCN)cc1OC
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Bromine (1.1 mL, 22 mmol) in acetic acid (10 mL) was slowly added into a vigorously stirred solution of 2-(3,4-dimethoxyphenyl)ethylamine (3.4 mL, 20 mmol) in 50 mL acetic acid. 2-bromo-4,5-dimethoxylbenzeneethanamine precipitated out after 15 minutes. The mixture was stirred for another two hours, filtered, and washed with dichloromethane 10 mL×3 and petroleum ether 10 mL×3. The resulting solid was taken up in water and the pH was brought to 10 with aqueous KOH solution. Extraction with dichloromethane followed by evaporation of the solvent yielded 4.12 g (78%) 2-Bromo-4,5-dimethoxylbenzeneethanamine. The crude product was dried under dynamic vacuum overnight and used without further purification.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C1CCN2C(=NCCC2)CC1.CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:35]([OH:41])[CH2:36][O:37][CH2:38][CH2:39]O>CN(C=O)C>[OH:41][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCOCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1OCCOCCO
Temperature: 80 °C
Yield: 74 %

Procedure:
To a stirred solution of N-hydroxyphtalimide (4.3 g, 26.2 mmol) in dry DMF (mL) was added DBU (4.0 g, 26.2 mmol). To this dark red solution was added monotosylate of diethylene glycol (6.8 g, 26.2 mmol). The reaction mixture was heated at 80° C. overnight, concentrated in vacuo, dissolved in ethyl acetate (200 mL) and extracted with saturated sodium bicarbonate until the aqueous phase was colorless. The organic phase was evaporated and dried by coevaporation with toluene. The title product was obtained after purification by flash silica gel chromatography as white solid. Yield 74%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].Cl[C:7]1[N:12]=[C:11]([Cl:13])[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12>>[Cl:13][C:11]1[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]2=[C:7]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: COCCN
Product: COCCNc1nc(Cl)nc2c1cnn2C

Procedure:
Reaction of 2-methoxyethylamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-methoxy-ethyl)-amine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:17]#[N:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].Cl.[NH2:31][OH:32]>C(O)C>[Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][C:14]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)([C:17]([NH:31][OH:32])=[NH:18])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C(=N)NO)(c2ccc(Cl)cc2)CC1

Procedure:
In a 4 mL vial was added 50 mg of 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile (0.1 mmol, 1.00 eq), 24 mg hydroxylamine hydrochloride (0.33 mmol, 3.00 eq), 94uL TEA (0.66 mmol, 6.00 eq), and 500uL ethanol. The mixture was heated to 55C overnight and the solvent removed in vacuo. The crude material was used “as is” in the following step:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][N:4]=1.CC([O-])=O.[Na+].[Br:16]Br.[OH-].[Na+]>CC(O)=O.O>[Br:16][C:10]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: BrBr
Reactant: COc1ccc(C=O)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ncc(C=O)cc1Br
Temperature: 90 °C
Yield: 39.2 %

Procedure:
To a mixture of 6-methoxynicotinaldehyde (3 g, 0.0219 mol) and NaOAc (3.5 g, 0.0427 mol) in HOAc (10 mL) was added a solution of bromine (1.64 mL, 0.031 mol) in HOAc (10 mL) over 30 mins via an additional funnel. The mixture was heated to 90° C. for 5 h, cooled to rt. The reaction was added iced water (100 mL), neutralized to pH=7.5 with aq. NaOH (5 N), extracted with ethyl acetate (4×50 mL), washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified via flash column using dichloromethane as an eluent. The product containing fractions were collected and concentrated to give 5-bromo-6-methoxynicotinaldehyde (1.854 g, 39% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][CH:20]=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[C:31]1(=[N:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:34][CH2:33][CH2:32]1>O1CCCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]3[CH:16]=[C:15]([C:17]4[S:21][C:20]([C:31]5([NH:35][S:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[O:37])[CH2:32][CH2:33][CH2:34]5)=[N:19][CH:18]=4)[CH:14]=[C:13]([CH3:22])[CH:12]=3)[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)S(=O)N=C1CCC1
Reactant: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C3CC3)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC3)s2)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a solution of the product of Step 1 (250 mg, 0.81 mmol) in tetrahydrofuran (5.0 mL) at −78° C. was added LDA (1.62 mL, 2.0 M, 3.24 mmol). The mixture was stirred for 15 min at −78° C. N-cyclobutylidene-2-methylpropane-2-sulfinamide (169 mg, 0.97 mmol) in tetrahydrofuran (3 mL) was added dropwise at −78° C. and the reaction was allowed to warm to room temperature and stirred over 2 h. The mixture was quenched with aqueous ammonium chloride and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic fractions were washed with brine, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexanes) provided 182 mg (0.38 mmol, 47%) of N-[1-(5-{3-[(4-cyclopropylpyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide. MS ESI: [M+H]+ m/z 482.2.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH:3]([OH:6])[CH2:4][CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl>[CH3:15][S:16]([O:7][CH:2]([CH:3]([O:6][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4][CH3:5])[CH3:1])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(O)C(C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(OS(C)(=O)=O)C(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Pentane-2,3-diol 1.04 g (10.0 mole) and triethylamine 2.23 g (22.0 mole) were dissolved in 40 mL of methylene chloride, and methanesulfonyl chloride 2.52 g (22.0 mole) was dropwise added thereto in a range of 0 to 5° C. and stirred at 0° C. for 30 minutes. After the raw materials were confirmed to be exhausted by gas chromatography analysis, the organic layer was washed with 20 ml of water and then 20 ml of a saturated salt solution. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was refined by column chromatography (Wako Gel C-200, hexane/ethyl acetate=2/1 eluted) to obtain 2.24 g of pentane-2,3-diyl dimethanesulfonate (pale orange liquid; novel compound) which was the targeted product (yield: 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.B([C:20]1[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>O>[O:11]=[C:6]1[C:5]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:20]3[N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:22]=[CH:23][CH:24]=3)[CH:3]=2)[NH:7]1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: O=C1Nc2ccc(Br)cc2C12CCCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one (3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere was added tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol%). After 15 min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq, 3.31 g, 15.6 mmol) and a solution of K2CO3 (2.3 eq, 3.83 g, 27.6 mmol) in water (5 mL) were added sequentially. The solution was heated to 80° C. for 3 h and allowed to cool. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (150 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash columm chromatography on silica gel (eluting with 30% EtOAc/hexane) to give subtitled compound: (3.4 g, 76%) as a white powder, mp 177° C. 1H NMR (CDCl3; 300 MHz) δ 1.38 (s, 9H), 1.59-1.93 (m, 10 H), 6.18 (m, 1H), 6.23 (‘t’, 1H, 3 Hz), 6.91 (d, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.34 (m, 1H), 7.44 (s, 1H), 8.33 (br s, 1H, D2Oex). MS ((+)-APCI) m/z 367 [(M+H)+]. Anal. Calcd for C22H26N2O3: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C@H:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C@@H:11]3[CH2:28][CH2:29][CH2:30][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(CC)CC>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.CN(C=O)C>[N:22]1([CH2:21][CH2:20][CH2:19][O:18][C:14]2[CH:13]=[C:12]3[C:17]([C@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:3]=4)[CH2:9][N:10]4[CH2:30][CH2:29][CH2:28][C@H:11]43)=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
To a high-pressure reaction vial was added cis-6-(3-iodo-phenyl)-9-(3-piperidin-1-yl-propoxy)-1,2,3,5,6,10b-hexahydro-pyrrolo[2,1-a]isoquinoline (Example 32, 40.0 mg, 0.08 mmol), trimethylsilylacetylene (9.0 mg, 0.093 mmol), Pd(PPh3)2Cl2 (6.0 mg, 0.008 mmol), Cul (2.0 mg, 0.008 mmol), PPh3 (4.0 mg, 0.016 mmol), Et2NH (0.12 mL, 1.2 mmol), and DMF (0.1 mL). The sealed vial was placed in a 120° C. preheated oil bath for 30 min, cooled to rt, concentrated under a stream of nitrogen, and purified by reverse-phase HPLC to give 27.0 mg (47%) of the desired product as a TFA salt. MS: exact mass calcd for C31H42N2OSi, 486.3; m/z found, 487.6 [M+H]+. 1H NMR (acetone-d6): 7.46 (m, 2H), 7.36 (m, 2H), 6.97 (d, J=2.5, 1H), 6.80 (dd, J=2.6, 8.7, 1H), 6.65 (d, J=8.7, 1H), 4.92 (m, 1H), 4.63 (m, 1H), 4.14 (t, J=6.0, 2H), 3.95 (m, 1H), 3.66 (m, 3H), 3.51 (m, 1H), 3.41 (m, 1H), 3.31 (m, 2H), 2.95 (m, 3H), 2.32 (m, 5H), 1.89 (m, 5H), 1.50 (m, 1H), 0.22 (s, 9H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:4]1[C:12]([O:14]CC)=O.C(=O)([O-])O.[Na+].[CH2:22]([NH2:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[CH2:22]([N:28]1[CH2:2][CH:3]2[CH:4]([CH:5]2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:12]1=[O:14])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CBr)C1c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCN1CC2C(C1=O)C2c1ccccc1
Temperature: 150 °C
Yield: 79.5 %

Procedure:
To a solution of ethyl 2-(bromomethyl)-3-phenylcyclopropanecarboxylate (Preparation 26, 65 mg, 0.22 mmol) in N,N-dimethylformamide (2 ml) was added sodium hydrogen carbonate (30 mg, 0.36 mmol) and hexylamine (33 μl, 26 mg, 0.26 mmol), and the mixture was heated to 150° C. for 3 h. The mixture was cooled, water (30 ml) was added, and the mixture was extracted with diethyl ether (2×30 ml). The extracts were combined, dried (Na2SO4), filtered and concentrated in vacuo. The mixture was purified by silica column (5 g) chromatography eluting with 4:1 dichloromethane:ethyl acetate. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (45 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH:38]([NH:41][CH3:42])([CH3:40])[CH3:39]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:41]([CH:38]([CH3:40])[CH3:39])[CH3:42])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNC(C)C
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC(C)N(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and N-isopropylmethylamine according to conditions described in general procedure C. Mp: 94-96° C.; 1H NMR (400 MHz, CDCl3) δ 1.06-1.14 (m, 6 H), 2.84 (s, 3 H), 3.25 (t, J=4.0 Hz, 4 H), 3.87 (t, J=4.8 Hz, 4H), 5.95 (d, J=5.2 Hz, 1 H), 6.78 (d, J=11.2 Hz, 1 H), 7.07 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1 H), 7.49-7.59 (m, 3 H), 7.89 (d, J=8.8 Hz, 1 H), 7.96 (d, J=7.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1 H), 8.14-8.17 (m, 2 H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:32](I)([CH3:34])[CH3:33]>C1COCC1.CN(C=O)C>[CH:32]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH2:23][O:24][CH3:25])[N:20]=[CH:19]3)[CH:12]=[C:7]12)([CH3:34])[CH3:33]
Reactant: COCc1cn(C2=NCC(=O)N3CCc4c(O)cccc4C3=C2)cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCc1cn(C2=NCC(=O)N3CCc4c(OC(C)C)cccc4C3=C2)cn1
Temperature: 25 °C
Reaction time: 17 h
Yield: 48 %

Procedure:
Example 142. To a stirred suspension of 9-hydroxy-2-(4-(methoxymethyl)-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (50 mg, 0.148 mmol) and cesium carbonate (120 mg, 0.369 mmol) in THF (1 mL) and DMF (0.35 mL), isopropyl iodide (55 mg, 0.325 mmol) was added. The mixture was stirred at rt for 17 h and poured onto H2O. The mixture was extracted with DCM and the combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by by SFC (column: PPU 5 μm, 250×30 mm, 60A, Princeton; eluent: 5% MeOH/CO2 isocratic run for 20 min; flow 100 mL/min; UV detection at 220 nm). The residue was crystallized from diethyl ether and gave the title compound as white crystals (27 mg). UPLC-MS: MS 381.2 (M+H+); UPLC rt 0.98 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.11 Hz, 6 H), 2.80 (t, J=6.11 Hz, 2 H), 3.23 (s, 3 H), 3.82 (br. s., 2 H), 4.22 (br. s., 2 H), 4.27 (s, 2 H), 4.64 (dt, J=12.04, 6.08 Hz, 1 H), 7.14 (d, J=8.07 Hz, 1 H), 7.22 (s, 1 H), 7.31 (t, J=8.19 Hz, 1 H), 7.63 (s, 1 H), 7.66 (d, J=7.82 Hz, 1 H), 8.20 (s, 1 H).
Reaction SMILES: [CH2:1]([N:3]([CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([OH:9])=O)[CH3:2].Cl.Cl.[NH2:27][CH2:28][C:29]1[C:30](=[O:40])[NH:31][C:32]([CH3:39])=[CH:33][C:34]=1[C:35]([F:38])([F:37])[F:36].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH2:1]([N:3]([CH:18]1[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]1)[C:4]1[C:5]([CH3:17])=[C:6]([CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:12]=1)[C:7]([NH:27][CH2:28][C:29]1[C:30](=[O:40])[NH:31][C:32]([CH3:39])=[CH:33][C:34]=1[C:35]([F:36])([F:37])[F:38])=[O:9])[CH3:2]
Reactant: CCN(c1cc(C(F)(F)F)cc(C(=O)O)c1C)C1CCN(C)CC1
Reactant: Cc1cc(C(F)(F)F)c(CN)c(=O)[nH]1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)NCc2c(C(F)(F)F)cc(C)[nH]c2=O)c1C)C1CCN(C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a stirred solution of 3-[ethyl(1-methylpiperidin-4-yl)amino]-2-methyl-5-(trifluoromethyl)benzoic acid (crude material, ˜0.313 mmol) and 3-(aminomethyl)-6-methyl-4-(trifluoromethyl)-1,2-dihydropyridin-2-one hydrochloride HCl salt (100 mg, 0.91 mmol) in DMSO (2.4 mL) was added PyBOP (248 mg, 1.05 mmol) and hunig base (166 ul, 2.10 mmol). The reaction mixture was stirred at rt for 16 hours. The reaction mixture was quenched with water and resulting precipitate was collected. The solid was triturated from ethylacetate/hexane. The resulting solid was purified by silica gel column chromatography (NH—SiO2 ethylacetate/MeOH=10/1+10% triethylamine). The crude compound was triturated from ethylacetate/hexane, and dried to give the titled compound as a white solid (75.0 mg, 44% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.32 (s, 1H), 7.26 (s, 1H), 6.86-6.89 (m, 1H), 6.34 (s, 1H), 4.73 (d, J=6.4 Hz, 2H), 3.08 (q, J=7.2 Hz, 2H), 2.80-2.85 (m, 2H), 2.70-2.78 (m, 1H), 2.37 (s, 3H), 2.35 (s, 3H), 2.24 (s, 3H), 1.85-1.89 (m, 2H), 1.69-1.72 (m, 4H), 0.84 (t, J=7.2 Hz, 3H); MS (ES) [M+H] 533.1, [M+Na] 555.2; HPLC 95.8% purity.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(C1C=CC=CC=1)C.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].C(OOC(C)(C)C)(=O)C.C([O-])(=O)CCCCCC(C)(C)C>C(C(C)=O)C.CC1CCC(=C(C)C)CC=1>[CH:1]([CH:19]=[CH:18][C:17]([OH:21])=[O:20])=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(=O)O
Reactant: C=Cc1ccccc1
Agent: CC(=O)OOC(C)(C)C
Agent: CC(C)(C)CCCCCC(=O)[O-]
Agent: CC1=CCC(=C(C)C)CC1
Solvent: CCc1ccccc1
Solvent: CCC(C)=O
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 95 °C
Reaction time: 1 h

Procedure:
Blend B Copolymer--Into a polymerization reactor equipped with an agitator and a reflux condenser were charged 616 ml of styrene, 3.0 grams of terpinolene and 200 ml of ethylbenzene. Then 80 grams of high cis-polybutadiene from Goodyear Tire & Rubber Company (Budene 1208) was dissolved in the mixture. After the rubber had dissolved, a solution of 40 grams of acrylic acid in 60 ml of methyl ethyl ketone was introduced into the mixture. The temperature of the reaction mixture was raised to 95° C. and maintained between 95° and 120° C. during the course of the polymerization. Polymerization was initiated by introducing into the system a mixture of 0.2 ml of tert-butyl peracetate and 0.2 ml of tert-butyl per-neo-decanoate. About one hour later, continuous addition of a solution of 40 grams of acrylic acid and 60 ml of methyl ethyl ketone was initiated and this addition was continued for about 4.5 hours. Additional 0.2 ml portions of tert-butyl peracetate were introduced into the polymerization mixture at 110 minutes and 310 minutes after the initiation of polymerization. Polymerization was terminated 5.5 hours after initiation and the resultant polymer was recovered and dried, first in air and then in a vacuum oven, to yield 432 grams of rubber-modified styrene-acrylic acid graft copolymer. In order to produce enough copolymer for the ensuing test work this general procedure was repeated five more times and the products from the six runs were combined and mixed in a Waring blender. Variations in the polymerization conditions occurred from run to run but were not of material significance. The resultant combined polymer contained about 84.6% styrene and about 15.4% acrylic acid. Its rubber content was approximately 17.1% based on the weight of the resin phase.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:26][CH3:27])=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][O:30][CH2:31][C:32](Cl)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:27][O:26][C:8]1[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:28])=[CH:16][C:15]2[N:14]=[CH:13][C:12]3[N:17]=[C:32]([CH2:31][O:30][CH3:29])[N:18]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[C:11]=3[C:10]=2[CH:9]=1
Reactant: COCC(=O)Cl
Reactant: COc1cc2c(NCc3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(pyridin-2-ylmethyl)quinoline-3,4-diamine (for a preparation see Intermediate 63, 500 mg) was dissolved in DCM (20 ml) and the reaction mixture was cooled to 0° C. 2-Methoxyacetyl chloride (1.1 eq) was added dropwise and the reaction mixture was stirred at room temperature for 30 min. The mixture was hydrolysed using a solution of sodium hydrogen carbonate and extracted with DCM. The organic was dried over Na2SO4, filtered and concentrated to dryness. The obtained residue was dissolved in acetic acid (5 ml) and the reaction mixture was heated to 130° C. for 16 h. The reaction mixture was treated with sodium hydroxide (1M) and extracted with DCM. The organic was dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, eluting with DCM/methanol (95:5). The resulting compound was recrystallised from acetonitrile and dried under vacuum to give 4-(8-methoxy-2-(methoxymethyl)-1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl)-3,5-dimethylisoxazole (50 mg) as a cream-coloured powder.