Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[C:17]([NH2:20])[CH:18]=[CH:19][C:14]=3[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10]2)[N:5]=[CH:4]1.[CH3:33][N:34]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:35]1[C:36](O)=[O:37]>>[ClH:1].[ClH:1].[ClH:1].[CH3:33][N:34]1[CH2:42][CH2:41][CH2:40][CH2:39][CH:35]1[C:36]([NH:20][C:17]1[CH:18]=[CH:19][C:14]2[CH2:13][N:12]([C:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)=[O:22])[CH2:11][CH2:10][N:9]([CH2:8][C:6]3[N:5]=[CH:4][NH:3][CH:7]=3)[C:15]=2[CH:16]=1)=[O:37]
Reactant: Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2
Reactant: CN1CCCCC1C(=O)O
Agent: Cl
Product: CN1CCCCC1C(=O)Nc1ccc2c(c1)N(Cc1c[nH]cn1)CCN(C(=O)c1cccc3ccccc13)C2

Procedure:
Example 90 was prepared as a light yellow solid from Example 26 and N-methyl-pipecolic acid as described for Example 62.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH2:4][CH2:3]1>C1COCC1>[CH2:3]([SiH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)[CH2:4][CH2:3]1)[CH2:4][CH2:5][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: Fc1ccc(C2CC[SiH](Cl)CC2)cc1F
Solvent: C1CCOC1
Product: CCCCCCC[SiH]1CCC(c2ccc(F)c(F)c2)CC1
Yield: 93 %

Procedure:
3.0 g (20 mmol) of 1-bromo-n-heptane was dropped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain Grignard reagent. This reagent was then dropped into a 50 ml THF solution of 4.9 g (20 mmol) of 4-(4-chloro -4-silacyclohexyl)-1,2-difluorobenzene to obtain 4-(4-n-heptyl -4-silacyclohexyl)-1,2-difluorobenzene. The product was a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 5.3 g of the trans isomer (yield 93%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:25](O)=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][CH:29]1[CH:34]([CH3:35])[CH2:33][CH2:32][CH:31]([NH2:36])[CH2:30]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH3:28][CH:29]1[CH:34]([CH3:35])[CH2:33][CH2:32][CH:31]([NH:36][C:25](=[O:26])[C@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:30]1
Reactant: CC1CCC(N)CC1C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC1CCC(NC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)CC1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.7 %

Procedure:
N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine (0.3 g) and 3,4-dimethylcyclohexylamine (0.1 g) were dissolved in dry methylene chloride (30 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.2 g) was added to the solution, followed by stirring at room temperature for 12 hours. According to a conventional post-treatment, N-(t-butyloxycarbonyl)-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide (I) (0.32 g) was obtained. The above compound (I) (0.3 g) was allowed to react with 4N-hydrogen chloride/dioxane solution to obtain 4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide hydrochloride (II) (0.26 g). The above compound (II) (0.26 g) and 4-(t-butyloxycarbonyl)aminomethylbenzoic acid (0.16 g) were dissolved in dry methylene chloride (20 ml)-pyridine solution, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) was added to the solution. The reaction was carried out at room temperature for 12 hours. After a conventional post-treatment, N-[4-(t-butyloxycarbonyl)aminomethylbenzoyl]-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide (III) (0.23 g) was obtained. The above compound (III) was allowed to react with 4N-hydrogen chloride/dioxane solution to (2 ml) obtain N-(4-aminomethylbenzoyl)-4-benzyloxy-L-phenylalanine 3,4-dimethylcyclohexylamide hydrochloride (0.18 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:39])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2I)[C:25](=[O:31])[C:26]#[C:27][CH:28]([CH3:30])[CH3:29])[CH:18]=1>>[CH3:14][O:15][C:16](=[O:39])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)/[C:26](=[C:27](\[C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)/[CH:28]([CH3:30])[CH3:29])/[C:25]2=[O:31])[CH:18]=1
Reactant: COC(=O)c1cccc(CN(C(=O)C#CC(C)C)c2ccccc2I)c1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(/c3ccc(C(F)(F)F)cc3)C(C)C)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 84 starting from 4-trifluoromethyl-phenylboronic acid (commercially available) and 3-{[(2-iodo phenyl)-(4-methyl-pent-2-ynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (DMSO, 300 MHz) δppm 7.90 (s, 1H), 7.79-7.86 (m, 2H), 7.58 (d, 1H), 7.48 (t, 1H), 7.42 (d, 1H), 7.09 (t, 1H), 7.00 (d, 1H), 6.89 (d, 1H), 6.65 (t, 1H), 5.65 (d, 1H), 5.03 (s, 2H), 4.84-4.93 (m, 1H), 3.57 (s, 3H), 0.96-1.06 (dd, 6H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)[C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[C:11]3[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1OC
Reactant: Cc1ncc[nH]1
Product: COc1ccc(CNc2nc(-n3ccnc3C)nc3sc(C(F)(F)F)cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with yields 2-chloro-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-trifluoromethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[O:11])[CH2:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dissolved in 300 ml of ether was 30.0 g (0.20 mole) of 2 -adamantanon and 7.3 g (0.19 mole) of lithium aluminum hydride suspended in 150 ml of ether was added. The mixture was stirred for 2 hours at room temperature (25° C). After 2-N-HCl was added to make it acidic and the water layer was extracted with dichloromethane, it was washed together with the ether layer and dried with sodium sulfate. The solvent was removed by evaporation at reduced pressure to obtain white powder. The test results were as follows:
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:13]=3[Cl:12])[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc(Cl)cc1Cl

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 2,4-dichlorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.91-1.99 (m, 3H), 2.04 (s, 1H), 2.21-2.33 (m, 4H), 3.44 (s, 2H), 3.55 (s, 4H), 4.41 (s, 1H), 7.41-7.49 (m, 2H), 7.54-7.59 (m, 1H); MS (APCI/NH3) m/z 325 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][N:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([B:30]([OH:32])[OH:31])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:12]1([N:4]2[C:5]3=[CH:6][N:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([C:27]3[CH:28]=[CH:29][C:24]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:25][CH:26]=3)=[CH:3]2)[CH2:16][CH2:15][CH2:14][CH2:13]1.[O:17]([C:24]1[CH:29]=[CH:28][C:27]([B:30]([OH:32])[OH:31])=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Nc1nncc2c1c(Br)cn2C1CCCC1
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: OB(O)c1ccc(Oc2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Product: Nc1nncc2c1c(-c1ccc(Oc3ccccc3)cc1)cn2C1CCCC1
Temperature: 85 °C

Procedure:
A mixture of 3-bromo-1-cyclopentyl-1H-pyrrolo [2,3-d]pyridazin-4-amine (0.057 g, 0.178 mmol), 4-phenoxyphenyl boronic acid (0.057 g, 0.266 mmol), sodium carbonate (0.062 g, 0.588 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.011 mmol) in ethylene glycol dimethyl ether (3 mL) and water (1.5 mL) was heated at 85° C. under an atmosphere of nitrogen for 2.5 hours. The mixture was cooled to ambient temperature and the solvent evaporated under reduced pressure. The residue was purified by preparative reverse phase HPLC to give the title compound contaminated with 4-phenoxyphenyl boronic acid. The residue was partitioned between dichloromethane and 5 N aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to give the title compound (14 mg, 21%); 1H NMR (DMSO-d6, 400 MHz) δ 8.98 (s, 1H), 7.68 (s, 1H),, 7.50 (d, 2H), 7.40 (t, 2H), 7.17 (t, 1H), 7.09 (m, 4H), 5.76 (bs, 2H), 5.01 (m, 1H), 2.19 (m, 2H), 1.91 (m, 2H), 1.71 (m, 2H); 5%–100% acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr20.60 min.; LC/MS: MH+ 371.2.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][CH2:8][C:9]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)=[O:10])([CH3:6])=[O:5])[CH3:2].[NH2:20][C:21]1[CH:26]=[C:25]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH:24]=[CH:23][C:22]=1[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:38][C:35]([O:34][C:33]([NH:32][C:22]1[CH:23]=[CH:24][C:25]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)=[CH:26][C:21]=1[NH:20][C:15]([C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH2:7][P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2])=[CH:19][CH:18]=1)=[O:17])=[O:39])([CH3:36])[CH3:37]
Reactant: CCOP(C)(=O)CCC(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(C)(=O)CCC(=O)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1

Procedure:
4-{3-[(ethyloxy)(methyl)phosphoryl]propanoyl}benzoic acid (1 g, 3.52 mmol), 1,1-dimethylethyl [2-amino-4-(2-thienyl)phenyl]carbamate (1.532 g, 5.28 mmol), DIPEA (0.922 mL, 5.28 mmol) and BOP (2.334 g, 5.28 mmol) were stirred in DMF (10 mL) at room temperature overnight. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with water and brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-20% MeOH-EtOAc) gave ethyl {3-[4-({[2-[({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]-3-oxopropyl}methylphosphinate as an orange solid. MS: cal'd 457 (MH+-Boc), exp 457 (MH+-Boc).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH3:19])[O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:22]2[N:23]=[C:24]([NH2:40])[C:25]3[N:26]=[CH:27][N:28]([C:38]=3[N:39]=2)[C@@H:29]2[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]2[OH:31])[CH2:9][CH2:8]1)=[O:11]
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C)c(C)c2)CC1
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Cc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1C

Procedure:
3,4-Dimethylphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.430 g, 5.27 mmol) was added to a solution of 2-iodoadenosine (0.620 g, 1.577 mmol) according to general procedure 2: yield 252 mg, 30%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.08 (d 1H, J=8.2 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.78 (dd, 1H, J=2.4, J=8.1 Hz), 5.93 (d, 1H, J=6.5 Hz), 4.71 (dd, 1H, J=5.1 Hz, J=6.5 Hz), 4.38-4.27 (m, 2H), 4.25-4.14 (m, 2H), 3.89 (dd, 1H, J=2.3 Hz, J=12.6 Hz), 3.74 (dd, 1H, J=2.6, J=12.6 Hz), 3.04, 2.90 (2×br t, 2H), 2.46 (d, 2H, J=6.2 Hz), 2.23, 2.22 (2×s, 6H), 2.02-1.79, 1.52-1.26 (2×m, SH). 13C NMR (CD3OD) δ 157.3, 155.8, 150.8, 150.2, 147.5, 142.6, 138.8, 134.7, 131.1, 123.7, 120.5, 119.9, 91.4, 88.3, 86.7, 82.3, 75.5, 72.6, 63.5, 45.5, 36.5, 32.5, 26.5, 19.8, 19.1. LRMS ESI (M+H+) 537.2. HPLC rt=10.9 min.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:11]([CH2:15][CH2:16][CH3:17])[C:12](Cl)=[O:13])[CH2:9][CH3:10].[CH2:18]([O:20][C:21]#[CH:22])[CH3:19]>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:18]1[C:11]([CH2:15][CH2:16][CH3:17])([CH2:8][CH2:9][CH3:10])[C:12](=[O:13])[CH:19]=1)[CH3:22]
Reactant: C#COCC
Reactant: CCCC(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC1(CCC)C(=O)C=C1OCC
Reaction time: 48 h
Yield: 66.6 %

Procedure:
The title compound was prepared using a modification of the method of Wasserman, H. H. et al, [J. Org. Chem, 38, 1451-1455, (1973)]; triethylamine (29 ml) was added dropwise at room temperature to a well-stirred solution of di-n-propylacetyl chloride (13.9 g, 85.8 mmol) and ethyl ethynylether (15 g, 40% solution in hexanes, 85.7 mmol) in toluene (120 ml. The reaction was warmed to 60° and stirred for 48 h prior to cooling and filtration. The filtrate was concentrated in vacuo and the residual oil chromatographed (SiO2; hexanes 80:EtOAc 20) to give the title compound as a brown oil (11.2 g, 57.1 mmol, 67%). δH (CDCl3, 300K) 5.02 (1H, s), 4.32 (2H, q, J 7.1 Hz), 1.69-1.61 (4H, m), 1.45-1.40 (4H, m), 1.02 (6H, t, J 7.3 Hz). m/z (ES+, 70V) 197.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[CH2:7].C(=O)([O-])[OH:14].[Na+].Cl[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.[Ni].ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]1[O:14][CH2:7]1
Reactant: O=C([O-])O
Reactant: C=Cc1ccc(OC)c(OC)c1
Agent: [Ni]
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C2CO2)cc1OC

Procedure:
Mixture: 27.2 g (160 mmol) of 3,4-dimethoxystyrene, 600 ml of dichloromethane, 220 ml of sodium hydrogen carbonate solution, 7.1 g of benzyltributylammonium chloride, 1.15 g (3.5 mmol) of nickel-salene, 900 ml of 13% strength sodium hypochlorite solution.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C:15]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][CH3:34])[C:25]2=[O:35])[CH2:20][CH2:19]1)([CH3:17])[CH3:16])=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][CH3:34])[C:25]2=[O:35])[CH2:20][CH2:19]1)([CH3:17])[CH3:16]
Reactant: CCn1c(=O)n(C2CCN(C(C)(C)CCCNC(=O)OCc3ccccc3)CC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCn1c(=O)n(C2CCN(C(C)(C)CCCN)CC2)c2ccccc21
Reaction time: 48 h

Procedure:
A solution of 1-(5-benzyloxycarbonylamino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine (93 mg, 0.19 mmol) in methanol (8 mL) containing chloroform (0.04 mL, 0.05 mmol) and 10% palladium/carbon (45 mg) was hydrogenated at atmospheric pressure for two days. The catalyst was removed by filtration, the solvent evaporated and the residue redissolved in chloroform. This solution was washed with aq. Na2CO3, dried (Na2SO4) and evaporated to give 1-(5-amino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([B:15]([OH:17])[OH:16])[CH:10]=2)=[N:7][C:2]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: OB(O)c1cccc(Nc2nc(Cl)ncc2F)c1
Product: OB(O)c1cccc(Nc2nc(Nc3cccc(O)c3)ncc2F)c1

Procedure:
In a like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-dihydroxyborylphenyl)-4-pyrimidineamine and 3-hydroxyaniline were reacted to produce 5-Fluoro-N4-(3-dihydroxyborylphenyl)-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.68 (bs, 1H), 9.35 (bs, 1H), 9.22 (bs, 1H), 8.10 (d, 1H, J=3.9 Hz), 7.88-7.80 (m, 2H), 7.54 (d, 1H, J=7.2 Hz), 7.31 (t, 1H, J=7.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.98-6.93 (m, 2H), 6.35 (d, 1H, J=8.4 Hz); LCMS: purity: 96%; MS (m/c): 341 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([N:6]([S:8]([NH:11][C:12](=[O:20])OC1C=CC=CC=1)(=[O:10])=[O:9])[CH3:7])(=[O:5])=[O:4].[CH3:22][C:23]1[CH2:27][CH:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[NH:25][N:24]=1>C1C=CC=CC=1>[CH3:21][N:2]([CH3:1])[S:3]([N:6]([S:8]([NH:11][C:12]([N:25]1[CH:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C:23]([CH3:22])=[N:24]1)=[O:20])(=[O:9])=[O:10])[CH3:7])(=[O:4])=[O:5]
Reactant: CC1=NNC(c2cccs2)C1
Reactant: CN(C)S(=O)(=O)N(C)S(=O)(=O)NC(=O)Oc1ccccc1
Solvent: c1ccccc1
Product: CC1=NN(C(=O)NS(=O)(=O)N(C)S(=O)(=O)N(C)C)C(c2cccs2)C1
Yield: 76.7 %

Procedure:
A mixture comprising 1.69 g (5.0 mmol) of phenyl N-[(N-dimethylsulfamoyl-N-methylamino)sulfonyl]carbamate, 0.58 g (3.5 mmol) of 3-methyl-5-(2-thienyl)-2-pyrazoline and 10 ml of dry benzene, was refluxed for 10 minutes. The mixture was left to cool, and then benzene was distilled off under reduced pressure. The obtained residue was washed with n-hexane. Then, the residue was stirred together with diethyl ether. The precipitated crystalline product was isolated by suction filtration and then washed with diethyl ether to obtain 1.1 g of the desired 1-[(N-dimethylsulfamoyl-N-methylamino)sulfonylcarbamoyl]-3-methyl-5-(2-thienyl)-2-pyrazoline.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:43])[C:6]([NH:29][CH:30]([C:37]2([CH3:42])[CH2:41][CH2:40][CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35]C)=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)#[N:2].C(C1C=C(F)C(N[C@@H](C2(C)CCCC2)CC(OCC)=O)=NC=1C1C2C(=NC=C(F)C=2)N(S(C2C=CC(C)=CC=2)(=O)=O)C=1)#N.C[O-].[Na+]>C1COCC1.C([O-])(O)=O.[Na+].CCOC(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([F:43])[C:6]([NH:29][C@@H:30]([C:37]2([CH3:42])[CH2:38][CH2:39][CH2:40][CH2:41]2)[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)#[N:2]
Reactant: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)c(C#N)cc1F)C1(C)CCCC1
Agent: CCOC(=O)C[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)c(C#N)cc1F)C1(C)CCCC1
Agent: C[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F)C1(C)CCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of racemic ethyl 3-(5-cyano-3-fluoro-6-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ylamino)-3-(1-methylcyclopentyl)propanoate, 144a, (0.150 g, 0.247 mmol) in THF (20 mL) was added sodium methoxide (0.053 mL of 25% wt solution in MeOH, 0.247 mmol). The reaction mixture was stirred at room temperature for 5 minutes. The reaction mixture was diluted with aqueous saturated NaHCO3 solution and EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The product was purified by silica gel chromatography (40% EtOAc/Hexanes) to afford 90 mg of the desired product as a mixture of ethyl and methyl esters. The mixture was taken onto the next step without further purification: 1H NMR (400 MHz, CDCl3) δ 10.18 (s, 1H), 8.65 (dd, J=9.6, 2.5 Hz, 1H), 8.48 (d, J=2.8 Hz, 1H), 8.32 (s, 1H), 7.37 (t, J=14.1 Hz, 1H), 5.38 (d, J=7.9 Hz, 1H), 5.02 (td, J=9.8, 3.5 Hz, 1H), 3.54 (s, 3H), 2.80 (dt, J=15.8, 7.9 Hz, 1H), 2.57 (dd, J=14.9, 9.8 Hz, 1H), 1.80-1.57 (m, 7H), 1.43 (ddd, J=24.5, 14.1, 6.0 Hz, 3H), 1.08 (s, 3H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.60 minutes (M+H) 440.26.
Reaction SMILES: Br[CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>C(O)C>[C:23]([S:25][CH:2]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:3][C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])(=[O:26])[CH3:24]
Reactant: O=C(c1ccc(F)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(F)cc1

Procedure:
To a solution of 3.7 g. of 1-[3-bromo-3-(4-fluorobenzoyl)propionyl]-L-proline (Example 19) in 37 ml. of ethanol is added 1.37 g. of potassium thioacetate. The procedure of Example 12 is followed giving the desired product as 1.02 g. of a glass.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7](CC)[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([NH2:30])=[O:29])[C:22]([Cl:36])=[CH:21][N:20]=1>>[Cl:36][C:22]1[C:23]([NH:25][C:26]2[C:34]([CH3:35])=[CH:33][CH:32]=[CH:31][C:27]=2[C:28]([NH2:30])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: Cc1cccc(C(N)=O)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: Cc1cccc(C(N)=O)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-benzamide to yield an off-white solid (2.4%). LCMS: m/z=465.15 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.05 (s, 1H), 7.46 (m, 4H), 7.20 (m, 2H), 7.04 (s, 1H), 6.74 (d, 1H, J=8.6 Hz), 6.23 (bs, 1H), 5.81 (bs, 1H), 2.36 (m, 2H), 2.27 (s, 3H), 2.06 (m, 2H), 1.36 (s, 6H).