Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([Cl:9])=[N:7][OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(OCC)C>[CH3:19][S:20]([O:8][N:7]=[C:6]([Cl:9])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON=C(Cl)c1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
A solution of 9.8 g of 4-chlorobenzohydroximoyl chloride in 300 ml of diethyl ether was chilled to 5°. To it was quickly added 10.4 g of triethylamine and, after 5 minutes, a solution of 6.1 g of methanesulfonyl chloride in 30 ml of diethyl ether was added dropwise during 30 minutes. The mixture was stirred for 1 hour at 0°-5°, followed by 1 hour at ambient temperature. The mixture was again cooled to 5°, then filtered, and the filter cake was washed with cold ether. The filtrate and washes were combined and the other evaporated under reduced pressure to leave a yellow oil. The oil was crystallized from a mixture of benzene and hexane to give 7.8 g of N-(methanesulfonyloxy)-4-chlorobenzimidoyl chloride, m.p. 80°-82°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2].[CH:31]1[C:39]2[C:38]3[CH:40]=[CH:41][CH:42]=[CH:43][C:37]=3[O:36][C:35]=2[C:34](B(O)O)=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:43]2[C:37]3[O:36][C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:39]=4[C:38]=3[CH:40]=[CH:41][CH:42]=2)=[N:8][C:7]=1[CH2:12][N:13]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Reactant: OB(O)c1cccc2c1oc1ccccc12
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2cccc3c2oc2ccccc23)sc1C(=O)OCC

Procedure:
Prepared from 2-bromo-4-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-thiazole-5-carboxylic acid ethy ester, example 81(b), and dibenzo[b,d]furan-4-yl-boronic acid under conditions analogous to experimental example 81(c). MS: (+) m/z 589.4 (M+1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C@@:14]1([CH3:22])[NH:19][C:18](=O)[CH2:17][NH:16][C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([C@:14]1([CH3:22])[CH2:15][NH:16][CH2:17][CH2:18][NH:19]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@]1(Cc2ccccc2)NC(=O)CNC1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@]1(Cc2ccccc2)CNCCN1
Temperature: 25 °C

Procedure:
Lithium aluminum hydride (1 M in THF, 7.2 ml, 7.2 mmol) was added dropwise over 15 min to a solution of (R)-3-benzyl-3-methylpiperazine-2,5-dione (0.51 g, 2.4 mmol) in THF (20 ml) stirring at ambient temperature. After stirring at reflux for 6 h, the reaction was allowed to cool to room temperature and was slowly quenched with water (0.27 ml). Sodium hydroxide (1 N, 1.0 ml) and then water (0.10 ml) were added and the gelatinous solid was filtered rinsing with THF. The filtrate was evaporated in vacuo and the residue was transferred to a separatory funnel with EtOAc. Washing the organic layer with brine and drying with MgSO4 afforded product (0.38 g) after evaporation of the solvent. This was used in the next step without further purification. MS (ESI) 191 (M+H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][N:23]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(N3CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.2 %

Procedure:
1-(2-Chloro-phenyl)-5-[6-(piperazin-1-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 357, methanesulfonyl chloride (7.0 uL, 0.09 mmol), and triethylamine (41.0 uL, 0.30 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1.[OH:23]N1C(=O)C2=CC=CC=C2C1=O>>[CH3:1][O:2][C@H:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][C:7](=[O:23])[C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[OH:22])[CH2:4]1
Reactant: CO[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: CO[C@H]1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Yield: 53 %

Procedure:
3β-methoxyandrost-5-ene-17β-ol (27) was subjected to air oxidation in the presence of N-hydroxyphthalimide and the producT 3β-methoxy-17β-hydroxyandrost-5-ene-7-one (28) was obtained in 53% yield. An analytical sample was obtained by recrystallization from acetone-hexane, m.p. 202-4° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])([O-])=O>CCO>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Solvent: CCO
Product: N#Cc1cccc(Oc2ccccc2N)c1
Yield: 98.9 %

Procedure:
A solution of 3-(2-nitrophenoxy)benzonitrile (1.21 g, 5 mmol, 1.0 equiv) in 30 mL of EtOH was treated with SnCl2H2O (3.38 g, 3 equiv) at reflux for 4 h. The volatile was evaporated and the residue was redissolved in EtOAc, washed with saturated aqueous NaHCO3 and 1N NaOH. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-aminophenoxy)benzonitrile (1.04 g, 99%). MS found for C13H11N2O (M+H)+: 211.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[F:13].C(=[NH:27])(C1C=CC=CC=1)C1C=CC=CC=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+].Cl.[OH-].[Na+]>O1CCOCC1.C1COCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:13][C:3]1[CH:4]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:7][C:2]=1[NH2:27]
Reactant: Fc1cc(OC(F)(F)F)ccc1Br
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Nc1ccc(OC(F)(F)F)cc1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
A mixture of 4-bromo-3-fluoro(trifluoromethoxy)benzene (6.6 g, 26 mmol), benzophenone imine (6.4 mL, 38 mmol), Pd2(dba)3 (0.58 g, 0.64 mmol), Xantphos (1.5 g, 2.6 mmol) and sodium tert-butoxide (3.7 g, 38 mmol) in 1,4-dioxane (120 mL) was stirred at 100° C. under N2 atmosphere for 5 h. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (0/100-5/95 AcOEt/hexane) to give a yellow oil. The residual oil was dissolved in THF (150 mL), and 1 M HCl aqueous solution (50 mL) was added to the mixture. After stirring at room temperature for 1 h, the mixture was basified with 8 M NaOH aqueous solution and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (0/100-5/95 AcOEt/hexane) to give the title compound (4.2 g, 85% yield) as a pale yellow oil: 1H NMR (300 MHz, DMSO-d6): δ ppm 5.36 (2H, s), 6.75-6.85 (1H, m), 6.89-6.94 (1H, m), 7.12 (1H, dd, J=11.7, 2.3 Hz).
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.Cl.[CH3:24][C:25]1([NH2:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>>[CH3:22][C:3]1[C:2]([NH:31][C:25]2([CH3:24])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC1(N)CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1(C)CCOCC1
Temperature: 100 °C
Yield: 6 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol), 4-methyltetrahydro-2H-pyran-4-amine hydrochloride (49.1 mg, 0.324 mmol, Biofine International, Blaine, Wash.), and DIPEA (141 μl, 0.810 mmol), heating at 100° C. for 20 h. Purification by silica gel (100% DCM to 5% MeOH/DCM) provided 2-(2-methyl-3-((4-methyltetrahydro-2H-pyran-4-yl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6% yield). 1H NMR (400 MHz, MeOD) δ ppm 1.73 (s, 3H) 1.85-1.95 (m, 2H) 2.53 (d, J=13.50 Hz, 2H) 2.67 (s, 3H) 3.01 (t, J=7.14 Hz, 2H) 3.64 (t, J=7.14 Hz, 2H) 3.76-3.82 (m, 4H) 7.00 (s, 1H) 7.40 (t, J=7.82 Hz, 1H) 7.65 (dd, J=8.12, 1.27 Hz, 1H) 7.88 (dd, J=7.53, 1.27 Hz, 1H). MS (ESI, pos. ion) m/z: 392.1 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[C:8]([I:9])=[C:7]([C:10]([O:12][CH2:13]C)=[O:11])[N:6]([CH3:15])[N:5]=2)[CH2:3][CH2:2]1.CN1C(C(OC)=O)=CC(C2C=C[C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=N1.II>>[I:9][C:8]1[C:4]([C:1]2[CH:3]=[CH:2][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:5][N:6]([CH3:15])[C:7]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: CCOC(=O)c1c(I)c(C2CC2)nn1C
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)nn1C
Agent: II
Product: COC(=O)c1c(I)c(-c2ccc(C(F)(F)F)cc2)nn1C

Procedure:
This compound is prepared analogously to the preparation of ethyl 3-cyclopropyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate from methyl 1-methyl-3-[4-(trifluoromethyl)phenyl]-1H-pyrazole-5-carboxylate and iodine.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: Clc1ccc(Br)c(I)c1
Reactant: OB(O)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1ccc(Br)c(C2CC2)c1

Procedure:
A solution of cyclopropylboronic acid (2.104 g, 24.49 mmol), 1-bromo-4-chloro-2-iodobenzene (5.700 g, 17.96 mmol), potassium phosphate (13.86 g, 65.3 mmol), and PdCl2(dppf)-DCM adduct (0.667 g, 0.816 mmol) in 18 mL dioxane and 6 mL water was heated to 100° C. overnight. The reaction mixture was then diluted with DCM and washed with water. The organics were dried over MgSO4 and concentrated. The crude residue was used in the next step without purification. m/z (ESI) does not ionize in H+ mode.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][C:4]1(F)F.C1(CBr)CC1.[CH3:13][C:14]1[N:15]=[C:16]([N:24]2[CH2:28][CH2:27][NH:26][C:25]2=[O:29])[S:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:5]1([CH2:4][N:26]2[CH2:27][CH2:28][N:24]([C:16]3[S:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]([CH3:13])[N:15]=3)[C:25]2=[O:29])[CH2:3][CH2:2]1
Reactant: FC1(F)CC1CBr
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: BrCC1CC1
Product: CCOC(=O)c1sc(N2CCN(CC3CC3)C2=O)nc1C
Yield: 96 %

Procedure:
Following the procedure as described in Preparation 13, making variations as required to replace bromomethyl-2,2-difluorocyclopropane with cyclopropylmethyl bromide to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained in 96% yield: 1H NMR (300 MHz, CDCl3) δ 4.23 (q, J=7.2 Hz, 2H), 4.07 (t, J=7.8 Hz, 2H), 3.67 (t, J=7.8 Hz, 2H), 3.16 (d, J=6.9 Hz, 2H), 2.58 (s, 3H), 1.28 (t, J=7.2 Hz, 3H), 0.97-0.88 (m, 1H), 0.59-0.42 (m, 2H), 0.25-0.12 (m, 2H); MS (ES+) m/z 310.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:12]=[C:13]([CH:14]([OH:16])[CH3:15])[C:8]=3[N:7]=[CH:6]2)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[Cl:32][C:33]([Cl:37])([Cl:36])[C:34]#[N:35]>C(OCC)C>[Cl:32][C:33]([Cl:37])([Cl:36])[C:34](=[NH:35])[O:16][CH:14]([C:13]1[C:8]2[N:7]=[CH:6][N:5]([CH2:4][CH:1]3[CH2:3][CH2:2]3)[C:9]=2[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[CH:12]=1)[CH3:15]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2c1ncn2CC1CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(±)-1-(1-(Cyclopropylmethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethanol (0.283 g, 0.996 mmol) was dissolved in diethyl ether (13 mL), cooled to 0° C. and treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (341 μL, 2.27 mmol). The reaction was stirred for 10 min and treated with trichloroacetonitrile (300 μL, 2.93 mmol) dropwise over 10 min. The reaction was allowed to warm up to room temperature overnight and concentrated. Flash chromatography on silica gel (50% ethyl acetate/hexanes) gave 195 mg (45.6%) as an light yellow oil. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 8.33 (s, 1 H), 8.15 (s, 1 H), 7.69 (s, 1 H), 7.64 (s, 1 H), 6.81 (q, J=6.4 Hz, 1 H), 4.05 (d, J=7.0 Hz, 2 H), 1.82 (d, J=6.4 Hz, 3 H), 1.29-1.39 (m, 1 H), 0.70-0.80 (m, 2 H), 0.40-0.50 (m, 2 H); 19F-NMR (470 MHz, CHLOROFORM-D) δ ppm −61.19.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(C)CCCOc1ccccc1C=O
Reactant: Nc1ccccc1
Solvent: CCO
Product: CN(C)CCCOc1ccccc1C=Nc1ccccc1
Yield: 83.2 %

Procedure:
A solution of 15 g of 2-(3-dimethylaminopropoxy)benzaldehyde and 8.0 g of aniline (distilled over zinc dust) in 300 ml of ethanol is kept at room temperature for 22 hours, refluxed for 2 hours, and the solvent removed on a rotary evaporator. The residue (21.3 g) is distilled to give 17 g of an oil; boiling point 171°-175° C/0.2 mm of Hg.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[Se:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1>>[C:1]1([NH:7][C:11]([C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[Se:8][S:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccn1
Reactant: O=c1c2ccccc2[se]n1-c1ccccc1
Product: O=C(Nc1ccccc1)c1ccccc1[Se]Sc1ccccn1

Procedure:
Prepared similar to example 1 from 2,5 g (9,1 mmol) of 2-phenyl-1,2-benzisoselenazole-3(2H)-one and 1,2 g (10,8 mmol) of 2-mercaptopyridine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH:7]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[Na+].[Na+].CCCC>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.C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[N:12]1[CH:8]([C:6]2[CH:7]=[C:2]([C:39]3[CH2:38][CH2:37][N:36]([C:34]([O:33][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:35])[CH2:41][CH:40]=3)[CH:3]=[CH:4][C:5]=2[F:28])[CH2:9][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:23])[F:24])=[N:11]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(Br)ccc2F)c(F)c1
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: CCO
Solvent: CCCC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 88 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
5-(5-Bromo-2-fluoro-phenyl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (500.0 mg, 1.06 mmol) prepared in Step 5 of Preparation 8, 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridin-1-carboxylic acid tert-butyl ester (26.7 mg, 1.59 mmol), Pd(PPh3)4 (123.0 mg, cat.) and a 2N sodium carbonate solution (5.0 mL) were added to a mixed solvent of ethanol (5.0 mL) and 1,2-dimethylethane (20.0 mL). The reaction mixture was stirred at 88° C. for 2 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/15) to give 360.0 mg of the titled compound as a white liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:38]2[CH:39]=[N:40][N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:25])[CH2:19][CH2:18]3)=[C:11]([N+:35]([O-])=O)[CH:10]=2)=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[NH2:35][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:38]3[CH:39]=[N:40][N:41]4[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=34)[C:2]([Cl:1])=[CH:7][N:6]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH3:25])[CH2:21][CH2:22]1
Reactant: COc1cc(N2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCN(C(=O)[C@H](C)NC(=O)OC(C)(C)C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 69.7 %

Procedure:
A mixture of (S)-tert-butyl N-[1-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-1-oxopropan-2-yl]carbamate (Intermediate 60, 100 mg, 0.15 mmol), iron (51.4 mg, 0.92 mmol) and NH4Cl (5.74 mg, 0.11 mmol) was heated at reflux in ethanol (3 mL) and water (1 mL) for 1 h. Purification by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia provided material that was further purified by FCC, eluting with O-5% CH3OH in CH2Cl2 to give the title compound (65 mg, 68%) as a yellow solid; m/z: ES+ MH+ 622.58.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@H:17](O)[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]>ClCCl>[CH3:10][O:11][C:12]([C@H:14]1[CH2:18][C@@H:17]([F:7])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:13]
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
Add (diethylamino)sulfur trifluoride (10.5 mL, 80 mmol) to a −78° C. cooled solution of 4-(S)-hydroxypyrrolidine-N1,2-(R)-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.83 g, 40 mmol) in dichloromethane (60 mL). Stir 2 h, then remove cooling bath and stir 18 h at room temperature. Heat to reflux for 30 min, then cool in ice bath and add saturated aqueous sodium bicarbonate solution. Warm to room temperature, dry (magnesium sulfate), concentrate (350 mbar, 25° C.) and purify (silica gel chromatography, eluting with diethyl ether and dichloromethane) and then concentrate at 120 mbar at 25° C. to give the title compound as an oil (9.09 g, 92%).
Reaction SMILES: [CH2:1]([CH:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:21].OO>O>[CH2:1]([CH:5]([CH2:9][NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([OH:8])=[O+:7][O-:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(CNCCC(=O)O)C(=O)O
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: OO
Solvent: O
Product: CCCCC(CNCCC(=O)O)C(O)=[O+][O-]
Temperature: 50 °C

Procedure:
100 g butyl imino dipropionic acid (0.46 mol) from example 7a was dissolved in 100 g H2O, whereupon 0.10 g EDTA was added and the temperature was increased to 50° C. After 30 minutes 3.2 g (0.475 mol) 50% hydrogen peroxide was added by drops during 20 minutes and the mixture reacted for 2 hours at 75° C. under a reflux cooler. Then the water was evaporated at 40° C. until a slightly yellow-brown oil formed.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH:5]=[CH:6][C:7]#[N:8].[H-].C([Al+]CC(C)C)C(C)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C@H:30](N)[CH3:31])[CH:27]=[CH:28][CH:29]=1.[BH4-].[Na+]>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH2:7][NH:8][C@@H:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)[CH3:31])[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: Cc1cccc(C=CC#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH4-]
Agent: [H-]
Product: COc1cccc([C@@H](C)NCC=Cc2cccc(C)c2)c1

Procedure:
In a similar fashion, 3-methylcinnamonitrile was treated with diisobutyl aluminum hydride and the intermediate aluminum-imine complex treated with (R)-1-(3-methoxyphenyl)ethylamine. The intermediate imine was treated with ethanolic sodium borohydride. Work-up and chromatography yielded (R)-N-[3-(3-methylphenyl)prop-2-enyl]-1-(3-methoxyphenyl)ethylamine, 12G, as a clear, colorless oil; m/z (rel. int.) 281 (M+, 5), 266 (9), 176 (24), 146 (71), 135 (62), 131 (100), 115 (23), 105 (19), 91 (41), 77 (18).
Reaction SMILES: S(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(C)(=O)=O.C1(=O)[NH:27]C(=O)C2=CC=CC=C12.[K]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C1(C)C=CC=CC=1>[NH2:27][CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K]
Solvent: Cc1ccccc1
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Mesyloxy-1-benzhydrylazetidine (30.32 g, 95.5 mmol), potassium phthalimide (21.59 g, 116.53 mmol) and hexadecyl tributylphosphonium bromide (5.92 g, 11.7 mmol) were added to toluene (600 mL) and the mixture stirred at room temperature overnight. The reaction was then heated at reflux for 3 h. The solid was removed by filtration, washed with EtOAc and the combined organics then washed with H2O. After drying over Na2SO4, the organics were treated with charcoal and then concentrated to an oil. Addition of isopropyl ether induced crystallization of the product (16.37 g, 46%).