Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19](C=O)=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:35]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([OH:35])=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)Nc1ccc2c(c1C=O)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)Nc1ccc2c(c1O)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reaction time: 8 h
Yield: 66 %

Procedure:
A solution of {(2R)-8-formyl-7-[(methoxycarbonyl)amino]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (8.46 g, 20.0 mmole) in methylene chloride (250 mL) was added dropwise to a solution of 57-86% m-chloro-peroxybenzoic acid (11.5 g, 40-48 mmole) in methylene chloride (120 mL). The reaction was stirred under nitrogen overnight. After dilution to 300 mL with methylene chloride, the solution was washed with saturated sodium aqueous sodium bicarbonate (2×200 mL) and with brine (100 mL), dried over magnesium sulfate, filtered and evaporated to dryness in vacuum. A H1 NMR spectra of the crude product was taken and it was determined to be the intermediate formate ester. Hydrolysis was effected by stirring in methanol over basic alumina for 15 hours. After filtration of the mixture and evaporation of the filtrate in vacuum, the residue was purified by column chromatography on silica gel with 20% hexane/methylene chloride to remove the impurities and methylene chloride to elute the product. Combination of the product fractions and concentration in vacuum gave the (R)-enantiomer of the title compound as a dark green foam (5.41 g, 66%). 1H (CDCl3) doublet, 7.8 δ (2 H); doublet, 7.3 δ (2 H); doublet, 7.2 δ (1 H); broad singlet, 6.8 δ (1 H); doublet, 6.4 δ (1 H); broad singlet, 6.0 δ (1 H); multiplet, 4.4 δ(1 H); multiplet, 4.2 δ (3 H); multiplet, 4.0 δ (1 H); singlet, 3.8 δ (3 H); singlet, 2.4 δ (3 H).
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:21])/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].II.CS(C)=O>O1CCOCC1>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:2]=1[O:1][C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])=[CH:12][C:11]2=[O:21])([O-:10])=[O:9]
Reactant: Cc1ccccc1/C=C/C(=O)c1cccc([N+](=O)[O-])c1O
Agent: II
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cc(=O)c2cccc([N+](=O)[O-])c2o1

Procedure:
A mixture of (E)-1-(2-hydroxy-3-nitrophenyl)-3-o-tolylprop-2-en-1-one 21 (250 mg, 0.88 mmol), I2 (471 mg, 1.86 mmol), DMSO (0.5 ml) and 1,4-dioxane (10 ml) was heated at reflux for 5 h. The reaction mixture was concentrated and H2O was added. The resulting precipitate was collected by filtration, rinsed with pentane/EtOAc (1:1) and dried under vacuum to give 22 as a yellow solid.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[C:15]1([NH:21][C:22]([N:11]2[C:12]3[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)n1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 1000 %

Procedure:
Sodium hydride (802 mg, 20.0 mmol, 60% in oil) was suspended in N,N-dimethylformamide (40 ml); 5-nitroindole (2.50 g, 15.4 mmol) was added thereto; and the reaction mixture was stirred at room temperature for 30 minutes. Phenyl isocyanate (2.01 ml, 1.23 mmol) was added thereto, and the reaction mixture was stirred at room temperature for 1.5 hours. Water (80 ml) was added to the reaction mixture; the reaction mixture was stirred at room temperature for 30 minutes; and the precipitated crystals were filtered off, washed by water and diethyl ether one by one, and dried by means F of suction to yield the title compound (3.53 g, 12.3 mmol, 79.8%) as pale yellow crystals.
Reaction SMILES: N(O[CH2:4][CH2:5][CH:6](C)C)=O.[C:9]([OH:18])(=O)[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)N.[OH-].[Na+]>C(COC)OC>[CH:15]1[CH:16]=[C:10]2[C:11]([CH:6]3[O:18][CH:9]2[CH:4]=[CH:5]3)=[CH:13][CH:14]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CC(C)CCON=O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: C1=CC2OC1c1ccccc12
Yield: 51 %

Procedure:
Solutions of 20 ml of isoamyl nitrite in glyme (20 ml) and of 13.7 g of anthranilic acid in glyme (45 ml) were added simultaneously by drops to a refluxing mixture of glyme (50 ml) and furna (50 ml). Refluxing was continued for ten minutes and the brown solution was cooled, made basic with aqueous sodium hydroxide (1N), and extracted with petroleum ether. The extract was washed thoroughly with water, clarified with Norit®, dried, and evaporated to give an oil. The oil solidified on cooling to give 7 g (51% yield) of light yellow solid. Recrystalization of the yellow solid from petroleum ether gave colorless crystalline solid of 1,4-dihydronaphthalene1,4-endo-oxide (IIIa), m.p. 53°-54° C. (lit. m. p. 56° C.).
Reaction SMILES: C(NCC)C.C(O)=O.CC1(C)[O:17][C:15](=[O:16])[CH2:14][C:12](=O)O1.C(=O)[C:20]1[CH:29]=[CH:28][C:25]([O:26][CH3:27])=[C:22]([O:23][CH3:24])[CH:21]=1>>[CH3:24][O:23][C:22]1[CH:21]=[C:20]([CH2:12][CH2:14][C:15]([OH:17])=[O:16])[CH:29]=[CH:28][C:25]=1[O:26][CH3:27]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1ccc(C=O)cc1OC
Solvent: CCNCC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After dropwise adding 17.55 g (25 ml, 0.24 mol) of diethylamine to 27.6 g (22.6 ml, 0.6 mol) of formic acid under stirring and cooling, 7.2 g (0.05 mol) of Meldrum's acid and 8.3 g (0.05 mol) of veratraldehyde were added to the above mixture, then the procedure of Example 35 was followed.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[CH:15][C:16]([CH:19]=[CH2:20])=[N:17][CH:18]=1>>[CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:22])([F:11])[F:21])=[CH:18][N:17]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(N)cc1
Reactant: C=Cc1ccc(C(F)(F)F)cn1
Product: CC(C)c1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1

Procedure:
In analogy to the procedure described for the synthesis example 25 (step 1), the title compound (4-isopropyl-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 309.2 [M+H]+) was prepared from 4-isopropylaniline instead of 3,4-dimethylaniline and 5-trifluoromethyl-2-vinyl-pyridine.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@:25]3([CH2:31][O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[CH2:29][CH2:28][CH2:27][N:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C.CCOC(C)=O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][C@:25]1([C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)[CH2:31][O:32][Si:33]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:35])[CH3:36])[CH:40]([CH3:41])[CH3:42]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)[Si](OC[C@@]1(c2nnc3ccc(F)cn23)CCCN1C)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)[Si](OC[C@@]1(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CCCN1C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of Intermediate A (170 mg, 1.03 mmol) in DMF (4 mL) was added NaH (60% in oil, 103 mg, 2.59 mmol) and the mixture stirred at RT for 20 min, before Intermediate 85i (350 mg, 0.862 mmol) was added. This mixture was stirred at 60° C. for 4 h. The cooled mixture was diluted with EtOAc, washed with water (3×), brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound as a clear viscous oil (230 mg, 48%). LCMS (Method 1): Rt 2.28 min, m/z 550 [MH+].
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:30]1(B(O)O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:1][C:2]1([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:38]3[C:39]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(O)cc2)C2(O)CCCCC2)CC1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Oc3cccc4ccccc34)cc2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl]piperazine-1-carboxylate (120 mg, 0.30 mmol), naphthalene-1-boronic acid (54 mg, 0.31 mmol) in dry dichloromethane (2 mL) was added copper (II) acetate (19 mg, 0.10 mmol), triethylamine (71 □L, 0.51 mmol), and powdered 4 Å sieves (100 mg) was stirred at room temperature for 16 h, after which time the reaction was filtered through a pad of Celite®, which was washed with dichloromethane (20 mL), and concentrated in vacuo. The product was purified via Biotage Horizon (FLASH 25 S, silica, gradient from 10% EtOAc/hexane to 60% EtOAc/hexane) to yield tert-butyl 4-{2-(1-hydroxycyclohexyl)-2-[4-(1-naphthyloxy)phenyl]ethyl}piperazine-1-carboxylate as a colorless oil. MS (ESI) m/z 531; HRMS: calcd for C33H42N2O4+H+, 531.32173; found (ESI, [M+H]+), 531.3203.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[OH:6][CH:7]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]#[N:24])=[CH:25][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1CCCc1ccc(C#N)cc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: N#Cc1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Yield: 79.8 %

Procedure:
Analogous to the procedure described for Example 1A, Step E, 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzonitrile (257.6 mg, 0.525 mmol) was deprotected with TBAF (1M in THF, 0.79 mL, 0.79 mmol) over 24 h. Purification by medium pressure chromatography (1:1 EtOAc: hexanes to EtOAc to 1% MeOH in CH2Cl2 to 3% MeOH in CH2Cl2) provided 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzonitrile (157.8 mg). 1H NMR (CDCl3) δ7.56 (m, 2H), 7.26 (m, 7H), 3.80 (m, 1H), 3.67-3.55 (m, 2H), 2.98 (m, 1H), 2.80 (m, 1H), 2.65 (t, 2H), 2.43-2.24 (m, 2H), 2.08 (m, 1H), 1.89-1.33 (m, 9H); MS,375.3 (M−1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]#[N:15])=[N:6]1.C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:26]>CO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:26])[NH2:15])=[N:6]1
Reactant: [NH4+]
Reactant: N#Cc1nn(CCC(F)(F)F)c2ncccc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(CCC(F)(F)F)c2ncccc12
Temperature: 65 °C
Reaction time: 3 h

Procedure:
To the intermediate from Step A above (44.4 g, 185 mmol) in MeOH (16 mL) at rt was added sodium methoxide (13.98 g, 259 mmol). After stirring for 3 hours, acetic acid (42.3 mL, 739 mmol) and ammonium chloride (12.85 g, 240 mmol) were added to the reaction. The resulting slurry was heated to 65° C. and stirred for 4 hours. The reaction was then cooled to rt and quenched with EtOAc and saturated aqueous NaHCO3. The aqueous layer was removed and back extracted with EtOAc (4×). The combined organic layers were washed with 20% brine and dried over Na2SO4, filtered and the solvent removed under vacuum. EtOAc was added and the precipitated product was filtered and washed with methyl tert-butyl ether. The solid was dried at rt under vacuum oven overnight and the material used without further purification. 1H NMR (500 MHz, CH3OH-d4): δ 8.74 (d, J=4.57 Hz, 1H); 8.52 (d, J=8.32 Hz, 1H); 7.51 (dd, J=8.31, 4.44 Hz, 1H); 4.96 (t, J=6.91 Hz, 3H); 3.08-2.97 (m, 2H). m/z=258.3 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]([OH:11])[C@H:7]([OH:10])[CH2:8][OH:9].[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37](Cl)[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]>>[C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH2:25][CH2:26][NH:27][C:28](=[O:42])[C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([N:2]([CH3:1])[CH2:3][C@H:4]([OH:13])[C@@H:5]([OH:12])[C@@H:6]([OH:11])[C@H:7]([OH:10])[CH2:8][OH:9])[N:36]=4)=[CH:31][CH:30]=3)[CH:23]=2)[NH:18][CH:17]=1)#[N:15]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: CNC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CN(C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using N-methyl-(2 (S),3 (R),4 (S),5 (R),6-pentahydroxy-hexyl)-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21](Cl)(=[O:23])=[O:22])#[N:14]>>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)(=[O:23])=[O:22])#[N:14]
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Product: N#Cc1ccccc1S(=O)(=O)N1CCCC1c1ccc(F)cc1

Procedure:
The title compound, light green solid, m.p. 101° C. and MS: m/e=330 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2-cyano-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([CH:20]=[O:21])=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.O.O1CCC[CH2:24]1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]([CH:20]([OH:21])[CH3:24])=[CH:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cc1ccnc(Nc2cccc(-c3ccc(C=O)s3)n2)c1
Reactant: C1CCOC1
Solvent: O
Product: Cc1ccnc(Nc2cccc(-c3ccc(C(C)O)s3)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
3M-Methylmagnesium bromide ether solution (0.19 ml, 0.57 mmol) was added to a solution of 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiophene-2-carboaldehyde (70 mg, 0.24 mmol) in tetrahydrofuran (4 ml) cooled with ice, and after that the mixture was stirred at room temperature for 3 hours in an Ar stream. Water was added to the reaction solution and the solution was extracted with ethyl acetate and the organic layer was washed with a saturated brine and dried over anhydrous magnesium sulfate. Subsequently, the residue obtained by concentration in vacuo was washed with isopropyl ether, dried in vacuo and the title compound (46 mg, 62%) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[C:10]([NH:11][CH2:12][C:13]3[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=[CH:9][CH:8]=[CH:7][N:6]2[C:21]=1[CH3:22].[CH3:23][OH:24]>>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=1[CH2:12][NH:11][C:10]1[C:5]2[N:6]([C:21]([CH3:22])=[C:3]([CH2:2][O:24][CH3:23])[N:4]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CO
Reactant: Cc1cccc(C)c1CNc1cccn2c(C)c(CCl)nc12
Product: COCc1nc2c(NCc3c(C)cccc3C)cccn2c1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 44 %

Procedure:
2-chloromethyl-8-(2,6-dimethylbenzylamino)-3-methylimidazo[1,2-a]pyridine (0.3 g, 0.96 mmol) was solved in methanol (20 ml) and stirred for 20 h. at room temperature and refluxed for 20 min. The solvent was evaporated under reduced pressure and the residue was dissolved in methylene chloride and washed with a bicarbonate solution. The organic layer was separated, dried (Na2SO4) and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel using diethyl ether:petroleum ether (2:1) as eluent and crystallization from diethyl ether:petroleum ether (2:1) gave 0.13 g (44%) of the desired product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].C(O[CH:13](O)[CH:14]([F:16])[F:15])C.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:1][CH2:13][CH:14]([F:16])[F:15])[CH3:6]
Reactant: CCOC(CN)OCC
Reactant: CCOC(O)C(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(CNCC(F)F)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
A solution of 3 g (22.5 mM) of 1-amino-2,2-diethoxyethane, 3.1 g (24.8 mM) of difluoroacetaldehyde ethyl hemiacetal and 1 pellet of solid NaOH in 44 ml of toluene was heated at 120° C. with a Dean-Stark trap for 1.5 hours. The mixture is left to stand until it has cooled to room temperature and is concentrated in vacuo. The residue is diluted with 80 ml of methanol, and 3.4 g (90 mM) of sodium borohydride were added in small quantities. The reaction mixture is then stirred overnight, concentrated in vacuo and partitioned between ethyl acetate and water. The organic phase is isolated, dried (MgSO4) and concentrated in vacuo. 3.7 g of crude substance are obtained as a colorless oil. The residue is subjected to a flash chromatography on 40 g of SiO2 (elution with DCM/MeOH, gradient 1-8%). 3.1 g of the desired amine were obtained as a colorless oil.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11]1.C(OCC)C>CCCCCCC>[CH2:7]([O:6][C:4](=[O:5])[C:3]([C:14](=[S:15])[NH:13][CH:10]1[CH2:12][CH2:11]1)=[C:2]([NH2:1])[CH3:9])[CH3:8]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: S=C=NC1CC1
Solvent: CCCCCCC
Solvent: CCOCC
Product: CCOC(=O)C(C(=S)NC1CC1)=C(C)N
Temperature: 100 °C
Yield: 44.9 %

Procedure:
A mixture of 2.03 ml of ethyl 3-aminocrotonate (16 mmol) and 1.59 g of cyclopropyl iso-thiocyanate (16 mmol) was heated to 100° C. for 5 h. The reaction mixture was then cooled to 0° C. and diethyl ether (5 ml) and a small amount of heptane were added. An oily precipitate formed and after 5 min the solvents were decanted off. The remaining residue was triturated with a small amount of diethyl ether at 0° C. The precipitate was then filtered off and dried to give 1.64 g (45%) of 3-amino-2-cyclopropylthiocarbamoyl-but-2-enoic acid ethyl ester as a yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 0.60 (m, 2H), 0.76 (m, 2H), 1.11 (t, J=7.1 Hz, 3H), 1.90 (s, 3H), 3.28 (m, 1H), 3.97 (q, J=7.1 Hz, 2H), 7.24 (br s, 1H), 8.21 (br s, 1H), 9.79 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.I[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.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>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: Ic1ccccc1
Reactant: OB(O)c1cc(Br)cnc1F
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ncc(Br)cc1-c1ccccc1
Temperature: 90 °C
Yield: 49.7 %

Procedure:
A solution of 5-bromo-2-fluoropyridin-3-ylboronic acid (620 mg, 2.82 mmol) and 1-iodobenzene (292 μL, 2.6 mmol) in 1,4-dioxane (50 μL) was degassed via nitrogen bubble for 15 mins. Then the mixture was added Pd(PPh3)4 (150 mg, 0.13 mmol) and aqueous Na2CO3 (24 μL, 5.7 mmol) and heated to 90° C. for 30 mins. The reaction was cooled to room temperature and poured into ethyl acetate (50 mL). The mixture was extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated. The residue was purified via a flash column using 10% ethyl acetate in hexanes as an eluent. The product containing fractions were concentrated to give 5-bromo-2-fluoro-3-phenylpyridine (2.2) (326 mg, 49.8% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][C:11]([N:16]3[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]3)=[C:12]([CH3:15])[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[N:10]=[N:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[C:13]([CH3:14])[C:12]=3[CH3:15])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCN[C@H](C)C2)c1C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCN(c3nnc(-c4ccc(F)cc4)c(C)c3C)C[C@H]2C)cn1
Temperature: 110 °C
Yield: 63.6 %

Procedure:
Combine 3-(4-fluoro-phenyl)-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (522 mg, 1.73 mmol), 5-chloro-pyrazine-2-carboxylic acid methyl ester (360 mg, 2.07 mmol), diisopropylethylamine (900 μl, 5.19 mmol) and dioxane (3 mL) in a round bottom flask. Heat to 110° C. for 18 h. Concentrate reaction mixture and purify by column chromatography (0-100% ethylacetate/heptane gradient). Triturate product with acetonitrile to give 480 mg of (R)-4-[6-(4-fluoro-phenyl)-4,5-dimethyl-pyridazin-3-yl]-2-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (63%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:21][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[N:32]=[C:31]([C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:19]1)#[N:16].[CH3:58]NCC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[C:15]([CH2:17][C:18]1([N:44]2[CH:48]=[C:47]([C:49]3[C:50]4[CH:57]=[CH:56][NH:55][C:51]=4[N:52]=[CH:53][N:54]=3)[CH:46]=[N:45]2)[CH2:21][N:20]([C@@H:22]2[CH2:27][CH2:26][C@H:25]([O:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[N:32]=[C:31]([C:39]([N:41]([CH2:43][CH3:58])[CH3:42])=[O:40])[CH:30]=3)[CH2:24][CH2:23]2)[CH2:19]1)#[N:16]
Reactant: CN(C)C(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1
Reactant: CCNC
Solvent: O=C(O)C(F)(F)F
Product: CCN(C)C(=O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)nc(C(F)(F)F)n1

Procedure:
This compound was prepared by a procedure similar to that of Example 46 using 6-[(cis-4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}cyclohexyl)oxy]-2-(trifluoromethyl)pyrimidine-4-carboxylic acid (20.00 mg, 0.02866 mmol) (Example 46, Step 4) and N-methylethylamine, (4.41 mg, 0.0747 mmol). 1H NMR (300 MHz, CD3OD) δ 9.15 (s, 1H), 8.92 (d, 1H), 8.61 (s, 1H), 7.85 (d, 1H), 7.31 (d, 1H), 7.17 (s, 1H), 5.52 (m, 1H), 5.11 (d, 2H), 4.83 (d, 2H), 3.75 (s, 2H), 3.64-3.47 (m, 3H), 3.08 and 3.00 (2 s, 3H), 2.30 (m, 2H), 2.03 (m, 2H), 1.91-1.58 (m, 4H), 1.24 (t, 3H). MS (ES): 609(M+1).