Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.Cl.Cl.[NH2:66][C@H:67]1[CH:72]2[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]2)[CH2:68]1>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:13][CH2:14]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:66][C@H:67]5[CH:72]6[CH2:73][CH2:74][N:69]([CH2:70][CH2:71]6)[CH2:68]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N[C@@H]2CN3CCC2CC3)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (0.11 g, 0.25 mmol, 1 eq), DIPEA (0.17 mL) and TBTU (88 mg, 0.28 mmol, 1.1 eq) were added to 5 mL DCM and the resulting solution stirred at rt for 30 min before the addition of (S)-(−)-3-aminoquinuclidine dihydrochloride (60 mg, 0.30 mmol, 1.2 eq). The RM was then stirred at rt for 16 hours before diluting with DCM and washing sequentially with water (×2), 50% saturated aqueous sodium hydrogen carbonate, saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in the minimum quantity of EtOAc before addition of n-heptane to precipitate (S)-4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxy-N-(quinuclidin-3-yl)benzamide (white solid, 0.075 g, 55%).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=C[C:42]([O:43]C2C=NC=CC=2)=CC=1OC)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][C:25]=4[O:43][CH3:42])[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(Oc4cccnc4)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C#Cc1ccc(Oc2cccnc2)cc1OC
Product: COc1cc(Oc2cccnc2)ccc1-c1cn(C2CCc3c(F)cccc3N(CC(F)(F)F)C2=O)nn1

Procedure:
Prepared as for 6-fluoro-3-{4-[4-(pyridin-3-yloxy)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 3-(4-ethynyl-3-methoxyphenoxy)pyridine as the alkyne.
Reaction SMILES: [CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:1]1([C:7]2[CH:32]=[CH:31][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27]([NH:29][NH:30][C:40]([NH:39][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[O:41])=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C=Nc1ccccc1
Reactant: NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Solvent: C1CCOC1
Product: O=C(NNC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2)Nc1ccccc1
Reaction time: 4 h
Yield: 25.2 %

Procedure:
A mixture of 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-carboxylic acid hydrazide of Example 8 (0.56 g) and phenylisocyanate (0.17 g) in tetrahydrofuran (25 mL) was refluxed under stirring for four hours. After removal of all volatiles at reduced pressure, the residue was treated with water and extracted with dichloromethane. The combined extracts were dried over anhydrous sodium sulfate and the solution filtered through a short column of Magnesol®. After elution with several additional volumes of dichloromethane, the combined eluate was evaporated to dryness to provide the title compound as a yellow amorphous solid (0.18 g).
Reaction SMILES: [C:1]1(B(O)O)C=CC=CC=1.[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[N:25]=[C:26]([C:30]3[CH:31]=N[C:33](OC)=[CH:34][CH:35]=3)[C:27](F)=[CH:28][C:15]=2[CH2:14]1)(=[O:12])[CH3:11]>>[C:10]([N:13]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[CH:17][C:16]2[N:25]=[C:26]([C:30]3[CH:31]=[CH:1][CH:33]=[CH:34][CH:35]=3)[CH:27]=[CH:28][C:15]=2[CH2:14]1)(=[O:12])[CH3:11]
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Reactant: OB(O)c1ccccc1
Product: CC(=O)N1Cc2ccc(-c3ccccc3)nc2C=Cc2ccccc21
Yield: 87 %

Procedure:
The title compound (19.9 mg, 87%) was prepared from 13C (20.0 mg, 0.07 mmol) and phenylboronic acid (12.8 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.353 min; LCMS Found: (M+H)+=327.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[O:31])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1.[C:38]1(=O)[CH2:41][CH2:40][CH2:39]1>ClC(Cl)C>[CH:38]1([N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)[CH2:41][CH2:40][CH2:39]1
Reactant: O=C1CCC1
Reactant: O=C(C=Cc1ccc(OC2CCNCC2)cc1)N1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=C(C=Cc1ccc(OC2CCN(C3CCC3)CC2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
Sodium triacetoxyborohydride (38.6 grams, 0.18 moles) was added in a single lot to a well stirred solution of 3-[4-(Piperidin-4-yloxy)phenyl]-1-(morpholin-4-yl)prop-2-ene-1-one (19.1 grams, 0.060 moles, obtained in preparation 1) and cyclobutanone (6.8 mL, 0.09 moles) in dichloroethane (500 mL). The mixture was further stirred at room temperature for 6 hours. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was quenched on to water (1000 mL) and basified with 40% lye solution (pH˜9). The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic layer was washed with brine solution (250 mL), dried over sodium sulfate, concentrated under vacuum and the residual mass was further purified by flash chromatography using methanol:triethylamine:chloroform in the ratio of 1.5:0.25:98.25 to obtain the title compound (17.4 grams).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][N:27]1[CH2:31][C:32]1[S:36][C:35](B(O)O)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>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.O1CCOCC1>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:35]4[S:36][C:32]([CH2:31][N:27]5[CH2:28][CH2:29][CH2:30][CH:26]5[CH3:25])=[CH:33][CH:34]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CC1CCCN1Cc1ccc(B(O)O)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)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: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCCC5C)s4)cc23)CC1
Temperature: 150 °C
Reaction time: 0.13 h
Yield: 29.3 %

Procedure:
A solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (36 mg, 0.0862 mmol), {5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}boronic acid (19 mg, 0.0862 mmol) and potassium carbonate (71 mg, 0.517 mmol) was combined in a CEM microwave tube. To this mixture was added water (0.25 mL), dioxane (0.75 mL) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol). The vial was capped and reacted in a CEM microwave for 20 min at 150° C. To this reaction was added tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) and reacted in a microwave for 20 min at 150° C. Additional tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) was added, and the reaction was heated in the CEM microwave for an additional 20 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL H2O), eluting in sequence with water (3 mL), MeOH (9 mL), and a 2 M solution of NH3/MeOH (9 mL). The fraction containing crude product solution was concentrated under a stream of nitrogen, and the residue was taken up in DMSO (3 mL). This DMSO solution of crude product was purified as three separate injections (1 mL each) on the Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×50 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The two fractions containing product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns used per fraction) and concentrated under a stream of nitrogen at 40° C. to give 13 mg of the title compound (29.3%).
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(=O)C.[NH4+].[N+:15]([CH3:18])([O-:17])=[O:16]>C(O)(=O)C.O>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:18][N+:15]([O-:17])=[O:16]
Reactant: Cc1ccccc1C=O
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccccc1C=C[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
Ortho-tolualdehyde (10.00 g, 83.23 mmol) was dissolved in acetic acid (50 ml), ammonium acetate (6.93 g, 89.89 mmol) and nitromethane (7 ml, 129 mmol) were added, and the mixture was stirred at 110° C. for 8 hr and stood at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (12.71 g, yield 94%) as a bistered oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19](OC3C=CC([N+]([O-])=O)=CC=3)=[O:20])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)=[O:20])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:10])([F:12])[F:11]
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
A solution of 5.85 g (9.54 mmol, purity 80%) of the compound from Example 77A in 1-methyl-2-pyrrolidone (50 ml) was admixed with 5.43 ml (5.91 g, 57.2 mmol) of thiomorpholine and 4.99 ml (3.70 g, 28.6 mmol) of N,N-diisopropylethylamine and then heated in 4 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 45 min. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 4.29 g (93% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][C:18]=3[C:25]([F:28])([F:27])[F:26])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:32][S:33]([CH2:35][S:36][CH3:37])=[O:34].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:29])[C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[C:35](\[S:33]([CH3:32])=[O:34])/[S:36][CH3:37])=[CH:19][C:18]=3[C:25]([F:26])([F:28])[F:27])=[CH:12][CH:11]=2)=[CH:30][CH:31]=1
Reactant: CSCS(C)=O
Reactant: O=Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CS/C(=C/c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C(F)(F)F)c1)S(C)=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of N-(4-chlorophenethyl)-4-(4-formyl-2-(trifluoromethyl)phenoxy)benzamide (0.225 g, 0.502 mmol) in THF (5 ml) was added methylsulfinyl(methylthio)methane (0.125 g, 1.00 mmol) followed by benzyltrimethylammonium hydroxide (0.114 ml, 0.251 mmol) and the reaction was stirred at 70° C. for 1 hour. The reaction was cooled, loaded onto a silica gel samplet and the product was eluted using a gradient of 0.5% methanol/dichloromethane to 15% methanol/dichloromethane. Isolated (Z)—N-(4-chlorophenethyl)-4-(4-(2-(methylsulfinyl)-2-(methylthio)vinyl)-2-(trifluoromethyl)phenoxy)benzamide (0.220 g, 79.0% yield) which by TLC appeared to be a 4:1 mixture of olefin isomers. The crude material was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28](=[O:29])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]([OH:24])[CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)=[CH:34][CH:33]=1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)CCc1ccc(B(O)O)cc1
Product: CCOC(=O)CCc1ccc(-c2ccc(-c3onc(C)c3C(O)CCCc3ccccc3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-ol and [4-(2-ethoxycarbonylethyl)phenyl]boronic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl.N1C=CC=CC=1>[N:22]1([CH2:21][C@@H:17]2[CH2:18][CH2:19][CH2:20][N:16]2[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[N:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:15])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Procedure LL: To a stirring solution of [4-(6-amino-pyridin-3-yl)-phenyl]-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (1.0 mmol) in 3:1 dichloromethane/pyridine (0.10M), add methanesulfonyl chloride (1.3 mmol) and stir at room temperature for 48 hours. After this time, wash the reaction with 1N hydrochloric acid while extracting with dichloromethane. Using 2N sodium hydroxide, make the aqueous phase basic and extract with 10% isopropanol/dichloromethane. The product remains in the aqueous layer during the acid/base workup. Concentrate the aqueous layer in vacuo and purify the title compound via radial chromatography eluting with 2M ammonia and dichloromethane. MS (m/e): 429.2 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc(F)cc4)CC3)c(OC)nc2c1
Yield: 92 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 92%). 1H NMR (300 MHz, CDCl3): δ 3.17 (s, 4H), 3.75 (s, 4H), 3.89 (s, 3H), 4.12 (s, 3H), 6.86-7.01 (m, 4H), 7.13 (s, 2H), 7.32 (s, 1H), 7.72-7.74 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:14])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Product: O=C(Cl)c1cc(Cl)cc([N+](=O)[O-])c1Cl
Yield: 87.5 %

Procedure:
A mixture of 5.0 parts of 2,5-dichloro-3-nitrobenzoic acid and 16.2 parts of thionyl chloride was refluxed for 24 hours under argon. The reaction mixture was evaporated, yielding 4.74 parts (87.5%) of 2,5-dichloro-3-nitrobenzoyl chloride (interm. 66).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](=[S:40])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=S)NCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 120 °C
Yield: 27.4 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (99 mg, 0.208 mmol) in toluene (1 mL) was mixed with Lawesson's reagent (168 mg, 0.416 mmol) and refluxed at 120° C. for 1 hour. After cooling, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (28 mg, 27% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:34][CH3:35])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][C:22]2[N:27]=[CH:26][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][N:23]=2)[CH:9]=1)([CH3:3])[CH3:2].[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:40]Br.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[F:36][C:37]1[CH:38]=[C:39]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:40][N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:19])[F:18])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:34][CH3:35])[C:22]1[N:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[CH:24][N:23]=1
Reactant: Fc1cc(CBr)cc(C(F)(F)F)c1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CNc1ncc(N2CCOCC2)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
(5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (500 mg) is dissolved in N,N-dimethylformamide (3 ml), and thereto is added 3-fluoro-5-(trifluoromethyl)benzylbromide (528 mg) and thereto is added sodium hydride (60%) (82 mg) under ice-cooling, and the mixture is stirred at room temperature for 2 hours and a half. To the reaction solution are added a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=49:1→22:3) to give (3-fluoro-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amine (440 mg). MS (m/z): 663 [M+H]+
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[CH:7]1[CH:12]=CC=C[CH:8]=1>CC(C)=O>[CH3:8][C:7]1([CH3:12])[NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][O:4]1
Reactant: c1ccccc1
Reactant: CC(C)(N)CO
Solvent: CC(C)=O
Product: CC1(C)COC(C)(C)N1
Yield: 57 %

Procedure:
Firstly, the precursor compound (2,2,4,4-tetramethyl-1,3-oxazolidine was prepared. To 237 g (3.0 mole) of 2-amino-2-methyl-1-propanol, there was added approximately 750 ml of dry benzene containing 174 g (3.0 mole) of acetone.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[CH2:42][CH2:43]O>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:43][CH2:42][CH:38]3[CH2:39][CH2:40][CH2:41][N:37]3[CH3:36])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2cc(O)ccc2n1
Reactant: CN1CCCC1CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2cc(OCCC3CCCN3C)ccc2n1
Temperature: 35 °C

Procedure:
A mixture of 0.400 g (0.002 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 0.966 g (0.004 mmol) of triphenylphospine (Fluka), 0.396 g (0.003 mmol) of 1-methyl-2-pyrrolidineethanol and 0.68 ml (0.004 mmol) di-tert.-butyl azadicarboxylate 40% in toluene in 40 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH/NH4OH from 97/3/0.5 to 90/10/0.5. The ]
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[C:17](=[O:25])[C:16]([C:26]([OH:28])=[O:27])=[CH:15]1>N1C=CC=CC=1>[CH:1]([O:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH3:24])[N:22]=2)[C:17](=[O:25])[C:16]([C:26]([OH:28])=[O:27])=[CH:15]1)=[O:2]
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1
Reactant: O=CO
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Cc1ccc2c(=O)c(C(=O)O)cn(CCOC=O)c2n1
Temperature: 25 °C

Procedure:
Formic acid (1.1 ml) was added to acetic anhydride (2.2 ml) which was cooled to 0°-5°. The mixture was heated at 50° for 15 minutes, cooled to 0° and added to 1,4-dihydro-1(2-hydroxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.5 g) in pyridine (12 ml), also cooled to 0°. The mixture warmed to room temperature and after 1 hour the solid was collected, washed with pyridine and dried, m.p. 213°-214° (85 %).