Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[CH:5][C:4]([C:12]([F:15])([F:14])[F:13])=[N:3]1.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C1COCC1>[CH3:1][N:2]1[C:6]([C:7]2[S:8][C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][N:11]=2)=[CH:5][C:4]([C:12]([F:15])([F:13])[F:14])=[N:3]1
Reactant: Cn1nc(C(F)(F)F)cc1-c1nccs1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(-c2cc(C(F)(F)F)nn2C)s1
Reaction time: 1.5 h

Procedure:
2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole and THF at −50° C. or below, followed by stirring at −50° C. or below for 90 minutes. Ethyl chloroformate was added to the reaction solution at −20° C. or below. After stirring at −20° C. or below for 15 minutes, it was subjected to purification in the usual way to give ethyl 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylate. This was hydrolyzed with a base in the usual way to give 2-(1-methyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiazole-5-carboxylic acid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CCOC(C)=O>CN1CCCC1=O>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:11]=[C:10]([CH2:12][C:13]([NH2:15])=[O:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: NC(=O)Cc1cc(Cl)nc2ccccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(CC(N)=O)c3ccccc3n2)CC1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
2-(2-chloro-quinolin-4-yl)-acetamide (500 mg, 2.27 mmol) is dissolved in 1-methyl-2-pyrrolidinone (3.0 mL). N-methylpiperazin (1.3 mL, 5 eq.) is added and the reaction is stirred at 80° C. for 48 h. AcOEt (20 mL) is added and the precipitate is purified by FCC (AcOEtVEtOH/28% NH40H 80:18:1) to afford 2-[2-(4-methyl-piperazin-1-yl)-quinolin4-yl]-acetamide as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: N#Cc1cccc(N)c1
Product: N#Cc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-aminobenzonitrile, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 3.72 (s, 3H), 6.74 (m, 1H), 7.05 (m, 1H), 7.45 (m, 1H), 7.58 (br m, 2H), 7.83 (m, 1H), 7.88 (m, 1H), 8.19 (br s, 1H), 10.59 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([OH:17])=O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:22]([NH:24][CH:25]1[CH2:27][CH2:26]1)=[O:23]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([NH:18][C:19]2[CH:20]=[C:21]([C:22]([NH:24][CH:25]3[CH2:26][CH2:27]3)=[O:23])[CH:28]=[CH:29][C:30]=2[CH3:31])=[O:17])=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1ccc(OCc2ccccc2)cn1
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccc2)cn1

Procedure:
The title compound was prepared from 5-(benzyloxy)pyridine-2-carboxylic acid and 3-amino-N-cyclopropyl-4-methylbenzamide according to the method described for Example 1; NMR Spectrum: (DMSOd6) 0.58 (m, 2H), 0.69 (m, 2H), 2.32 (s, 3H), 2.86 (m, 1H), 5.32 (s, 2H), 7.39 (m, 4H), 7.51 (m, 2H), 7.57 (m, 1H), 7.71 (m, 1H), 8.13 (m, 1H), 8.22 (m, 1H), 8.36 (m, 1H), 8.48 (s, 1H), 10.16 (s, 1H); Mass Spectrum: M+Na+424.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20]C(N1CCC2(OCCO2)CC1)=O)(C)(C)[CH3:17].[Li]C(CC)C.CI>CN(CCN(C)C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([O:20][CH2:16][CH2:17][O:14]2)[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CI
Solvent: O
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)OCCO2
Reaction time: 1 h

Procedure:
2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was added and the mixture was warmed from −78° C. to RT over 16 h. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes) provided 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at 65° C. for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2 and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, the mixture was diluted with satd. aq. NaHCO3 and H2O, and extracted with CH2Cl2. Purification on SiO2 (120 g, 5 to 15% EtOAc/hexanes) provided 1.40 g of the desired product as a white solid. 1H NMR (500 MHz, CDCl3): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s, 9H), 1.11 (d, J=7.1 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([NH:23][C:24]4[N:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])[C:27]([Cl:43])=[CH:26][N:25]=4)=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:16]=3)[C:11]2=[O:44])[CH2:7][NH:6]1)=O.CO.[NH3:47]>>[Cl:43][C:27]1[C:28]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[S:37]([CH:40]([CH3:41])[CH3:42])(=[O:39])=[O:38])=[N:29][C:24]([NH:23][C:14]2[CH:13]=[C:12]3[C:17]([CH2:18][N:10]([C@@H:8]4[CH2:7][NH:6][C@H:5]([C:3]([NH2:47])=[O:2])[CH2:9]4)[C:11]3=[O:44])=[CH:16][C:15]=2[O:19][CH:20]([CH3:21])[CH3:22])=[N:25][CH:26]=1
Reactant: COC(=O)[C@@H]1C[C@H](N2Cc3cc(OC(C)C)c(Nc4ncc(Cl)c(Nc5ccccc5S(=O)(=O)C(C)C)n4)cc3C2=O)CN1
Reactant: N
Solvent: CO
Product: CC(C)Oc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)C(=O)N([C@@H]1CN[C@H](C(N)=O)C1)C2
Temperature: 25 °C

Procedure:
(2S,4S)-4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid methyl ester generated in Step 1 (20 mg, 0.03 mmol) is dissolved in 7 N ammonia solution in MeOH (3 mL, 21 mmol). The resulting solution is heated using microwave irradiation to 120° C. for 1 h. After cooling to room temperature, the reaction mixture is concentrated in vacuo, neutralized to pH=8 with saturated aqueous NaHCO3, and extracted with DCM. The organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo to give (2S,4S)-4-(6-{5-Chloro-4-[2-(propane-2-sulfonyl)-phenylamino]-pyrimidin-2-ylamino}-5-isopropoxy-1-oxo-1,3-dihydro-isoindol-2-yl)-pyrrolidine-2-carboxylic acid amide (177) as a yellow solid. 1H NMR 400 MHz (DMSO-d6 with trace D2O) δ 8.47 (d, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.78 (dd, 1H), 7.68 (m, 1H), 7.31 (t, 1H), 7.24 (s, 1H), 4.71 (m, 2H), 4.43 (dd, 2H), 3.60 (m, 1H), 3.44 (m, 1H), 3.35 (m, 1H), 2.63 (m, 1H), 2.28 (m, 1H), 1.22 (d, 6H), 1.10 (d, 6H); MS m/z 628 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C.[NH2:26][CH2:27][CH:28]1[CH2:30][CH2:29]1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:26][CH2:27][CH:28]2[CH2:30][CH2:29]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(Cl)n1
Reactant: NCC1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1cccc(Cl)n1
Reaction time: 2 h
Yield: 97.3 %

Procedure:
6-Chloropyridine-2-carboxylic acid (5.00 g, 31.7 mmol) was dissolved in DCM (100 mL) and DMF (0.5 mL) and oxalyl chloride (6.54 mL, 76.2 mmol) were added dropwise. The reaction mixture was stirred for 2 h, concentrated in vacuo and azeotroped with DCM. The residue was dissolved in DCM (100 mL), DIPEA (22.6 mL, 127 mmol) and aminomethylcyclopropane (5.51 mL, 63.5 mmol) were added dropwise and the reaction mixture was stirred for 4 h. The reaction mixture was washed with sat aq NaHCO3 solution (250 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (6.50 g, 97%) as a light brown gum. LCMS (ES+): 211.2 [MH]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:11]=1[NH2:12].C(=O)([O-])[O-].[K+].[K+]>C1(C)C(C)=CC=CC=1.CCCCCCC.[Cu]>[Cl:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[C:11]=1[NH:12][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(I)cc1
Reactant: Nc1c(F)cc(F)cc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: Cc1ccccc1C
Product: Cc1ccc(Nc2c(F)cc(F)cc2Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 4-iodotoluene (210 g, 0.96 mol), 2-chloro-4,6-difluoroaniline (204 g, 1.25 mol), copper powder (36 g, 0.57 mol), cuprous iodide (130 g, 0.68 mol), and potassium carbonate (118 g, 0.86 mol) in 500 ml of xylene is stirred vigorously and heated to reflux in a flask fitted with a Dean-Stark trap for 26 hours. After cooling to room temperature, the solids are filtered off, and the filter cake is washed with 100 ml of xylene. The solvents are evaporated under reduced pressure to give an oil which is dissolved in a mixture of 50 g of silica gel in 750 ml of heptane. The solids are filtered off and the solvents are evaporated under reduced pressure to give N-(2′-chloro-4′,6′-difluorophenyl)-4-methylaniline as an oil.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([Cl:32])=[C:23]([Cl:22])[CH:24]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Clc1ccc(CCBr)cc1Cl
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.3 g--see Preparation 8), 3,4-dichlorophenethyl bromide (0.27 g--see Preparation 14), anhydrous potassium carbonate (0.4 g) and acetonltrile (10 ml) was heated under reflux for 4 hours. On cooling to room temperature, water (40 ml) was added and the resulting mixture extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 7%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield, 0.22 g.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:26])=[O:25])=[C:21]([O:27][C@@H:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH3:29])[CH:20]=3)[C:12]=2[CH:11]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C@H:28]([O:27][C:21]1[CH:20]=[C:19]([N:18]2[C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[N:15]=[CH:14][C:13]=3[N:16]=[CH:17]2)[S:23][C:22]=1[C:24]([NH2:26])=[O:25])[CH3:29]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1.57 g of 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(1R)-1-(2-chlorophenyl)ethoxy]thiophene-2-carboxamide in 30 ml THF is cooled to 0° C. At 0° C., 1.05 ml tetra-n-butylammonium fluoride (˜75% in H20) are added. The reaction mixture is allowed to warm to room temperature and stirred for 90 minutes.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][CH:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])[CH:4]([NH:15][C:16](=[O:28])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:23]2[N:27]=[CH:26][CH:25]=[N:24]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CC(O)CC1NC(=O)c1ccccc1-n1nccn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(=O)CC1NC(=O)c1ccccc1-n1nccn1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl N-{4-hydroxy-2-[2-(2H-1,2,3-triazol-2-yl)benzamido]cyclopentyl}carbamate (910 mg, 2.35 mmol) in dry DCM (12 ml) at 0° C. under an atmosphere of nitrogen was added Dess-Martin periodinane (3.4 g, 7.99 mmol). The reaction was warmed to room temperature for 2 hours then concentrated in vacuo. The crude material was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4](=[O:6])[CH3:5].O1[CH2:11][CH2:10][CH2:9][CH2:8]1.[H-].[Na+].ClC/C=C\CCl>C(Cl)Cl>[CH3:1][S:2][C:3]1([S:4](=[O:6])[CH3:5])[CH2:11][CH:10]=[CH:9][CH2:8]1
Reactant: CSCS(C)=O
Reactant: C1CCOC1
Agent: ClC/C=C\CCl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CSC1(S(C)=O)CC=CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Formaldehyde dimethyl mercaptal S-oxide (1.27g) was dissolved in 15 ml. of tetrahydrofuran, and 246 mg of sodium hydride was added. The mixture was stirred for 30 minutes at room temperature, and then for 2 hours at 50° C. With ice cooling, 442 mg of cis-1,4-dichloro-2-butene was added. The mixture was stirred for 1 hour with ice cooling, and then for 6.5 hours at room temperature. Methylene chloride (100 ml) was added, and the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was separated by column chromatography (Florisil, eluted with methylene chloride) to afford 382 mg of 3-cyclopentenone dimethyl mercaptal S-oxide in a yield of 61%.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:31]([NH2:33])[CH3:32]>>[C:1]([N:8]1[CH2:15][C@@H:14]([N:16]([CH:23]2[CH2:28][CH2:27][C:26]([F:30])([F:29])[CH2:25][CH2:24]2)[C:17](=[O:22])[C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:13][C@H:9]1[C:10]([NH:33][CH2:31][CH3:32])=[O:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N(C(=O)C(C)(C)C)C2CCC(F)(F)CC2)C[C@H]1C(=O)O
Reactant: CCN
Product: CCNC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(F)(F)CC2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Step D of Example A1 using (4S)-1-BOC-4-[(4,4-difluorocyclohexyl)(2,2-dimethylpropanoyl)amino]-L-proline (0.95 g, 2.2 mmol) prepared in Step C of Example A5 and commercially available ethylamine (0.93 g, 93%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:22]2[CH2:24][CH2:23]2)=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=1)[C:6]=2[C:18]([NH:20][CH3:21])=[O:19].CCN(C(C)C)C(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].[OH-].[K+].Cl>C(Cl)Cl.CCO.O1CCOCC1>[CH:22]1([C:3]2[C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:10][C:9]3[C:5](=[C:6]([C:18]([NH:20][CH3:21])=[O:19])[N:7]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=4)[N:8]=3)[CH:4]=2)[CH2:24][CH2:23]1
Reactant: CNC(=O)c1c2cc(C3CC3)c(N)cc2nn1-c1ccc(C)cn1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: CNC(=O)c1c2cc(C3CC3)c(NS(C)(=O)=O)cc2nn1-c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a suspension of (v) (2.75 g, 8.6 mmol) in DCM (30 mL) at 0° C. was added DIPEA (4.40 mL, 25.0 mmol) followed by methanesulfonyl chloride (3.30 mL, 42.0 mmol). The reaction mixture was stirred at RT for 1 h and then washed with aq. sat'd. NaHCO3 (50 mL), brine (50 mL) and dried (MgSO4). Removal of solvent in vacuo gave the crude product, which was then dissolved in EtOH (100 mL) and 1,4-dioxane (20 mL). To the resultant solution was added KOH (˜10 eq) portionwise at RT until the pH 8-9 was achieved. The reaction mixture was then slowly neutralised by addition of 1M HCl (aq) and volatiles removed in vacuo. The residue was taken up in EtOAc (50 mL) and washed with water (50 mL). The organic phase was dried (MgSO4), concentrated in vacuo and the solid residue then triturated with EtOAc. The solid was separated by filtration and dried in a stream of air and purified further by automated column chromatography (Biotage SP4, 12 g Grace Resolve cartridge) eluting with EtOAc:n-heptane (gradient elution from 60% to 100%. v/v) to give Compound (2) (2.42 g, 72%). ESI-MS: calculated [M+H]+ 400.1 observed [M+H]+ 400.1. 1H NMR (400 MHz, CDCl3) δ 8.94 (brd, J=3.9 Hz, 1H), 8.38 (s, 1H), 7.99 (s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.86-7.77 (m, 2H), 7.17 (s, 1H), 3.18 (s, 3H), 3.09 (d, J=4.7 Hz, 3H), 2.50 (s, 3H), 1.84-1.76 (m, 1H), 1.15-1.04 (m, 2H), 0.84-0.74 (m, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:12][C:13]#[N:14].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C>[C:13]([CH2:12][N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2][CH2:3]1)#[N:14]
Reactant: N#CCCl
Reactant: OCCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCN1CCN(CCCO)CC1
Yield: 71.1 %

Procedure:
A solution of 3-(piperazin-1-yl)propan-1-ol (0.93 g, 6.45 mmol), chloroacetonitrile (0.58 g, 7.75 mmol), potassium carbonate (1.79 g, 12.9 mmol) and sodium iodide (0.32 g, 1.93 mmol) in DMF (10 ml) was stirred at ambient temperature overnight. The volatiles were removed under vacuum and the residue was purified by column chromatography eluting with ethylene chloride/methanol (95/5) to give 3-(4-cyanomethylpiperazin-1-yl)propan-1-ol (0.84 g, 71%).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:29][CH:6]2[CH:7]([C:19]3[CH:24]=[CH:23][C:22]([O:25]COC)=[CH:21][CH:20]=3)[O:8][C:9]3[CH:10]=[CH:11][C:12]([O:15]COC)=[CH:13][C:14]=3[CH:5]2[CH2:4]1)[CH3:2].Cl.CCOC(C)=O.CCOC(C)=O.CCCCCC>C1COCC1>[CH2:1]([C@H:3]1[CH2:29][C@H:6]2[C@@H:7]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)[O:8][C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][C:14]=3[C@H:5]2[CH2:4]1)[CH3:2]
Reactant: CCC1CC2c3cc(OCOC)ccc3OC(c3ccc(OCOC)cc3)C2C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC[C@H]1C[C@@H]2[C@H](C1)c1cc(O)ccc1O[C@@H]2c1ccc(O)cc1
Yield: 66.7 %

Procedure:
Dissolve alkyl cyclopentane 38 (109 mg, 0.27 mmol) in THF (4 mL) then add 3 M HCl (1.0 mL). Stir the reaction at room temperature overnight. Dilute the reaction with EtOAc and wash with saturated aqueous sodium bicarbonate and brine. Extract the aqueous layer with EtOAc (1×). Combine the organic extracts, dry (Na2SO4), filter and concentrate in vacuo. Purify by flash chromatography (10 g SiO2, dry loading on 700 mg silica, 40 ml/min, 0-30% EtOAc/Hexane over 25 minutes and then 30% EtOAc/hexane for 7 minutes) to afford 56 mg (0.18 mmol, 68%) of alkyl cyclopentane 39 as a white solid. HRMS(ES+) calcd for C20H26NO3: 328.1913; found: 328.1906 (M+NH4). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 9.33 min).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:11][C:3]1[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1Br
Product: Cc1cc(C(=O)O)ccc1-c1ccccc1

Procedure:
The title compound was prepared from 4-bromo-3-methylbenzoic acid and benzeneboronic acid using a similar procedure to Description 15, as a pale yellow solid (89%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].N([O-])=O.[Na+].O.O.O.C([O-])(=O)C.[Na+].[N-:29]=[N+:30]=[N-].[Na+]>C(O)(=O)C.Cl.O>[N:1]([C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
23.2 G (0.100 mol) of 2-amino-5-chloro-benzophenone [compare F. D. Chattaway, J. Chem. Soc. 85, 340 (1940)] are dissolved in 100 ml of glacial acetic acid and in 25 ml (0.3 mol) of 36% strength hydrochloric acid. 6.9 G (0.100 mol) of sodium nitrite dissolved in 25 ml of water are then added dropwise over the course of 15 minutes whilst stirring and cooling with water at 20°-25°C and 250 g of ice, 250 ml of water and 41.0 g (0.300 mol) of sodium acetate trihydrate are added to the solution. The turbid solution is clarified by filtration using charcoal and the filtrate is poured into a stirred solution of 16.2 g (0.250 mol) of sodium azide in 250 ml of glacial acetic acid. The resulting precipitate is filtered off, repeatedly washed with water and dried in vacuo over calcium chloride, after which 2-azido-5-chlorobenzophenone of melting point 81°-83°C is obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]3[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]3)[N:8]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].[CH2:30]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])[CH3:31]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:30]([O:32][C:33]([N:35]1[CH2:36][CH2:37][N:38]([C:2]2[S:6][C:5]([C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH:14]4[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]4)[N:8]=3)=[CH:4][CH:3]=2)[CH2:39][CH2:40]1)=[O:34])[CH3:31]
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(Br)s3)n2)CC(C)(C)N1
Reactant: CCOC(=O)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(c2ccc(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)s2)CC1

Procedure:
[4-(5-Bromo-thiophen-2-yl)-pyrimidin-2-yl]-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine (Step C of Example 5, 198 mg, 0.5 mmol), NaOtBu (53 mg, 0.55 mmol), R-(+)-BINAP (6.2 mg, 0.01 mmol), Pd(OAc)2 (6.2 mg, 0.027 mol) and N-ethoxycarbonylpiperazine (158 mg, 1.0 mmol) were refluxed in 1,4-dioxan for 18 hours. The reaction mixture was poured on water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, and purified via chromatography on silicagel (TBME/MeOH/ammonia:98/1.8/0.2 to 95/4.5/0.5) to give the title compound as yellow solid. Yield: 120 mg (50%).