Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:12][N:13]([O:16]CC2C=CC=CC=2)[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C@H:33]2[CH3:39])[N:3]=1.ClC1N=C(Cl)C(F)=C(Cl)N=1.C([O-])=O.[NH4+].[NH4+].[OH-].C>CO.CC#N.[OH-].[OH-].[Pd+2].CCCCCCC>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:30])[C@H:11]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:31])=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][C@H:33]2[CH3:39])[N:3]=1
Reactant: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c1F
Agent: [Pd+2]
Agent: Fc1c(Cl)nc(Cl)nc1Cl
Agent: O=C[O-]
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CO
Product: C[C@@H]1CN(C)CCN1c1nc(Cl)nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
To a solution of crude [(2R)-3-(2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (assumed 176.57 g, 314.1 mmol) in MeOH (800 mL) was added 20% Pd(OH)2/C (14.13 g). The mixture was hydrogenated under balloon pressure with monitoring every 30 min until the reaction was judged to be complete (7 h). The mixture was then filtered through a glass fiber filter with MeOH washes. The resulting dark filtrate was concentrated in vacuo and purified by preparative reverse phase chromatography (Luna C18 (2) column; 10 microns; 101.6 mm×250 mm; 250 nm UV detection; 480 mL/min; 40 mg/mL sample concentration; 4 g injection mass; mobile phase A: 300 mmol aqueous ammonium formate at pH 4.0; mobile phase B: MeCN; method: 28% B for 9 min; 90% B for 9 min; 28% B for 5 min). The product solution fractions were combined and adjusted to pH 6.8 with aqueous NH4OH, and then stirred with Darco (50% weight load based on crude product) for 30 min at room temperature. The solution was then filtered through Celite. The filtrate was concentrated to a volume of 3.5 L, and the pH was adjusted from 5.6 to 8.5 with NH4OH, affording an orange precipitate. The aqueous phase was extracted 3 times with EtOAc, and then the combined organics were washed with water and brine. The organics were dried (Na2SO4), filtered, and concentrated in vacuo to a volume of 1 L, producing a tan precipitate. An equal volume of heptane (1 L) was added, and the mixture was cooled to 0° C. for 1 h. Then the product was isolated by filtration, washing with heptane, and dried under reduced pressure at 50° C. for 20 h to provide [(2R)-3-(2-{2-chloro-6-[(2R)-2,4-dimethyl-1-piperazinyl]-5-fluoro-4-pyrimidinyl}hydrazino)-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (85.5 g, 57% yield for 2 steps) as a white solid. LCMS: (M+H)+: 472.2.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.CCOCC>C(Cl)Cl>[C:5]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([CH3:17])[CH3:8])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CN(C)c1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of acetic anhydride (11.5 mL, 12.45 g, 0.122 mol) in anhydrous CH2Cl2 (100 mL) was added N,N-dimethyl-1,4-phenylenediamine (11.37 g; 83.5 mmol) portion-wise over 30 min at 0° C. The mixture was allowed to gradually warm to room temperature and stirred for 24 hours. The solvent was removed under high vacuum to obtain a black residue which was stirred with Et2O (20 mL) at room temperature. The suspension was filtered and the solid washed with Et2O (3×20 mL). The solid residue was dried under high vacuum to obtain the intermediate N-acetyl-N′,N′-dimethyl-1,4-phenylenediamine as a black solid (12.8 g, 86%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH2:25])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][S:34]([CH3:33])(=[O:36])=[O:35])=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ncccc1CN1CCC(CC(=O)c2ccccc2N)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NS(C)(=O)=O)CC1
Reaction time: 2 h

Procedure:
120 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-aminophenyl)-2-oxoethyl]piperidine obtained in Example 64, 0.1 ml of triethylamine and 0.041 ml of methanesulfonyl chloride were dissolved in 2 ml of dichloromethane, and the mixture was stirred for 2 hours under ice-cooling. An aqueous sodium bicarbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 90 mg of the title compound as a yellow oil.
Reaction SMILES: C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[F:19][C:20]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:29].[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:30][CH2:29][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([N+:26]([O-:28])=[O:27])[C:20]=1[F:19]
Reactant: Cc1cccc([N+](=O)[O-])c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(CBr)c1F
Yield: 66.7 %

Procedure:
Benzoyl peroxide (10.7 g, 44 mmol) was added under reflux under nitrogen atmosphere to a solution of 2-fluoro-1-methyl-3-nitrobenzene (compound 2a-1) (68.2 g, 440 mmol) and N-bromosuccinimide (95.0 g, 528 mmol) in carbon tetrachloride (1500 mL), and the mixture was stirred under reflux for 5 hours. Impurities were then removed by filtration, and a crude product was obtained by vacuum concentration. It was then purified by column chromatography (hexane), and the title compound (68.7 g, 65%) was obtained as a yellow to light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][NH:38][CH:37]([C:41]([N:43]([CH3:45])[CH3:44])=[O:42])[CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:53][CH:54]([F:56])[F:55]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)[CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:53][CH:54]([F:56])[F:55])[CH:37]([C:41]([N:43]([CH3:44])[CH3:45])=[O:42])[CH2:36]1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCNC(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: FC(F)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)C(C(=O)N(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 87.9 %

Procedure:
4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-N,N-dimethylpiperazine-2-carboxamide (38 mg, 0.061 mmol, Example 563D) was taken up in DMF (0.5 mL) and Cs2CO3 (39.5 mg, 0.121 mmol) and 2-bromo-1,1-difluoroethane (5.79 μl, 0.073 mmol) were added. The reaction was heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was extracted 2× with water and once with brine, then dried over Na2SO4, filtered, and concentrated. 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg) was obtained as an orange glass. The crude material was taken onto the next step.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClC1C=C2C(=C(C(OCC3(C4C=CC(F)=CC=4)CCN(C)CC3)C(OC)=O)C=1)NN=C2.[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[C:47]([CH:49]([O:55][CH2:56][C:57]3([C:70]4[CH:75]=[CH:74][C:73]([F:76])=[CH:72][CH:71]=4)[CH2:62][CH2:61][N:60]([C:63](OC(C)(C)C)=O)[CH2:59][CH2:58]3)[C:50]([N:52]([CH3:54])[CH3:53])=[O:51])[CH:48]=1)[NH:45][N:44]=[CH:43]2>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:39][C:40]1[CH:41]=[C:42]2[C:46](=[C:47]([CH:49]([O:55][CH2:56][C:57]3([C:70]4[CH:71]=[CH:72][C:73]([F:76])=[CH:74][CH:75]=4)[CH2:58][CH2:59][N:60]([CH3:63])[CH2:61][CH2:62]3)[C:50]([N:52]([CH3:53])[CH3:54])=[O:51])[CH:48]=1)[NH:45][N:44]=[CH:43]2
Reactant: CN(C)C(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn[nH]c12
Agent: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(COC(C(=O)N(C)C)c2cc(Cl)cc3cn[nH]c23)(c2ccc(F)cc2)CC1

Procedure:
Prepared according to the procedure used to prepare methyl 2-(5-chloro-1H-indazol-7-yl)-2-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)acetate trifluoroacetic acid salt using tert-butyl 4-((1-(5-chloro-1H-indazol-7-yl)-2-(dimethylamino)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate as the starting material. 1H-NMR (CD3OD, 500 MHz) δ 8.53 (m, 0.1H), 8.07 (m, 0.8H), 7.98 (m, 0.1H), 7.81 (m, 0.8H), 7.45 (m, 1.7H), 7.36 (m, 0.5H), 7.29 (m, 0.9H), 7.14 (dd, J=8.9, 8.5 Hz, 1.6H), 7.03 (dd, J=8.9, 8.9 Hz, 0.5H), 5.52 (s, 1H), 3.91 (d, J=9.2 Hz, 0.2H), 3.35-3.66 (m, 4H), 2.50-3.00 (m, 14H), 1.90-2.25 (m, 2H). Mass spec.: 459.26 (MH)+.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[O:34]1[C:38]2[CH:39]=[CH:40][C:41](B(O)O)=[CH:42][C:37]=2[O:36][CH2:35]1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.C(Cl)Cl.O>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([C:2]3[S:10][C:9]4[C:8](=[O:11])[N:7]([CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:16][CH2:17]5)[C:6](=[O:25])[N:5]([CH2:26][C:27]5[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=5)[C:4]=4[CH:3]=3)=[CH:42][C:37]=2[O:36][CH2:35]1
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc5c(c4)OCO5)cc32)n1
Reaction time: 0.75 h

Procedure:
Tert-butyl 4-{6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (203 mg, B101), 1,3-benzodioxol-5-ylboronic acid (69 mg), dichlorobis(tricyclohexylphosphine)palladium (37 mg) and aqueous cesium carbonate solution (0.375 ml, 2.0 M) are placed in a microwave tube and DME (10 ml) is added. The reaction vessel is sealed and the mixture is subjected to microwave irradiation at 150° C. with stirring for 45 min. After addition of water and extraction with DCM the combined organic layers are washed with saturated aqueous sodium chloride solution and after filtration using a phase separator the organic layer is concentrated. The residue is purified by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] to afford the title compound as a solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:36])[CH2:34][NH2:35])[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.C[Si](C)(C)NC(=O)C.[Cl-].[CH3:46][O:47][C:48](=[O:58])[C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=O)=[CH:51][CH:50]=1.S([O-])(O)(=O)=O.[K+]>C(#N)C>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][CH2:27][C@H:28]([NH:32][C:33](=[O:36])[CH2:34][NH:35][C:53](=[O:55])[C:52]3[CH:51]=[CH:50][C:49]([C:48]([O:47][CH3:46])=[O:58])=[CH:57][CH:56]=3)[C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)NC[C@H](NC(=O)CN)C(=O)O)C2)CC1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CC(=O)N[Si](C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)c1ccc(C(=O)NCC(=O)N[C@@H](CNC(=O)[C@@H]2CCCN(C(=O)CCC3CCNCC3)C2)C(=O)O)cc1
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a stirred solution of N-[(3R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(2-aminoacetyl)amino-β-alanine (600 mg) and N-trimethylsilylacetoamide (770 mg) in acetonitrile (10 mL) was added terephtalic acid monomethyl ester chloride (233 mg) at 4° C. After stirring for 3 hours, the reaction mixture was acidified with 5% aqueous potassium hydrogensulfate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The organic layer was evaporated and the residue was treated with 4 N—HCl in ethyl acetate. The resulting insoluble material was collected by filtration, dried and dissolved in water. The solution was neutralized with an aqueous saturated sodium hydrogencarbonate solution, purified by ODS column chromatography (Daisogel-120sp®) eluting with 5, 10, 15 and 20% CH3CN/H2O and lyophilized to give N-[(3R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(2-((4-methoxycarbonylbenzoyl)amino)acetyl)amino-β-alanine (500.5 mg, 74.6%) as an amorphous powder.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].CS[C:14](=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:14]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[N:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NCc1ccc([N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Yield: 83.7 %

Procedure:
A solution of 4-nitrobenzylamine (5.24 g, 34.4 mmol) and S-methyl-N,N′-bis(tert-butoxycarbonyl)isothiourea (5.00 g, 17.2 mmol) in THF (60 ml) was stirred at 55° C. for 9 hours and at room temperature for 11 hours. The reaction mixture was concentrated under reduced pressure, was then mixed with ethyl acetate (150 ml) and was washed with 1 N hydrochloric acid (30 ml×3) and an aqueous saturated solution of sodium chloride (30 ml) in the order. The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, 150 g: ethyl acetate/hexane 1/9→1/6). The objective fractions were concentrated under reduced pressure, diisopropyl ether was added to the residue and an insoluble material was collected by filtration. The insoluble material was washed with diisopropyl ether and was then dried under reduced pressure to obtain N-(4-nitrobenzyl)-N′,N″-bis(tert-butoxycarbonyl)guanidine (5.67 g, 14.4 mmol, 83%)
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[C:6]([NH2:8])=[NH:7].C1O[C:17]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)OC1.CCOCC>C(O)C.Cl>[ClH:1].[ClH:1].[F:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:4]2[C:5]=1[C:6]([NH2:8])=[N:7][C:17]1([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[NH:3]2
Reactant: C1CC2(CCN1)OCCO2
Reactant: N=C(N)c1c(N)cccc1F
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: NC1=NC2(CCNCC2)Nc2cccc(F)c21
Yield: 169.3 %

Procedure:
To a solution of 2-amino-6-fluorobenzamidine dihydrochloride (Example C, 226 mg, 1 mmol) and 4-piperidone ethylene ketal (143 mg, 1 mmol) in dry ethanol (10 ml) was added IN HCl in ether (1 ml, 1 mmol) and the resulting mixture was heated at reflux for 36 h. The solid which separated on cooling was collected by filtration and recrystallised from ethanol to give the title compound (260 mg) as yellow crystals, m.p. 305°-307° C. (dec.).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[S:15][C:14]([NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[N:13][C:12]=1[C:27]([NH2:29])=[O:28].N1C=CC=CC=1>C1COCC1>[CH:1]1([CH2:6][C:7]([NH:10][C:11]2[S:15][C:14]([NH:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=3)=[N:13][C:12]=2[C:27]([NH2:29])=[O:28])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)CC1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A solution of 2-cyclopentylacetyl chloride (0.35 mL, 2.64 mmol) in THF (2 mL) was added dropwise to a mixture of 5-amino-2-(naphthalen-2-ylamino) thiazole-4-carboxamide (0.15 g, 0.53 mmol) and pyridine (2 mL) in THF (10 mL) at 0° C., and the mixture was stirred for 16 hrs at rt. The reaction mixture was quenched with ice-water. The resulting solids were collected by filtration and washed successively with ether and EtOAc to give 0.12 g (58% yield) of the titled compound.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:25])([CH3:24])[C:9](=[O:23])[C:10]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:11]2[OH:14])=[CH:6][CH:5]=1>C1COCC1.C(Cl)Cl>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:25])([CH3:24])[C:9](=[O:23])[C:10]([C:15](=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]2[OH:14])=[CH:6][CH:5]=1
Reactant: COC(=O)CCC(=O)C1=C(O)c2cc(Br)ccc2C(C)(C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC1(C)C(=O)C(C(=O)CCC(=O)O)=C(O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of aqueous NaOH (5M, 2.0 mL) was added to a solution of methyl 4-(7-bromo-1-hydroxy-4,4-dimethyl-3-oxo-3,4-dihydronaphthalen-2-yl)-4-oxobutanoate (0.061 g, 0.16 mmol) in THF (1.5 mL). The mixture was stirred for 15 minutes at room temperature, diluted with DCM, and extracted with water. The water phase was acidified to pH=1 using aqueous HCl (5M) and extracted with EtOAc. The combined organic layers were dried over MgSO4 and evaporated. The product was rinsed with diethyl ether and dried to afford the title compound in 31% yield. 1H-NMR (300 MHz, DMSO-d6) δ ppm 12.19 (1H, br. s.), 8.17, 8.16 (1H, 2 s), 7.91-7.88 (1H, m), 7.75-7.72 (1H, m), 3.45-3.35 (2H, m, partially covered by HDO signal), 2.60-2.56 (2H, m), 1.54 (6H, br. s.). MS m/z: 368 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=O)[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C@@:19]1([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:23][CH2:22][O:21][CH2:20]1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([NH:18][C@@:19]2([C:24]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])=[O:25])[CH2:23][CH2:22][O:21][CH2:20]2)=[O:17])[CH:12]=[N:13][CH:14]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C(=O)O)c1
Reactant: CCCCOC(=O)[C@]1(N)CCOC1
Solvent: C1CCOC1
Product: CCCCOC(=O)[C@]1(NC(=O)c2cncc(NC(=O)OC(C)(C)C)c2)CCOC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A suspension of 5-tert-butoxycarbonylamino-pyridine-3-carboxylic acid (2.5 mmol) in 20 mL tetrahydrofuran was combined with N,N-carbodiimidazole (2.75 mmol) and stirred for 15 minutes at ambient temperature. Then a solution of n-butyl(S)-3-amino-tetrahydrofuran-3-carboxylate (2.5 mmol) in 4 mL tetrahydrofuran was added and the reaction mixture was stirred further overnight. Then the solvent was distilled off and the crude product thus obtained was purified by chromatography (silica gel; dichloromethane with 1-25% ethanol).
Reaction SMILES: [CH3:1][C:2]([OH:34])([C:4]#[C:5][C:6]1[CH:7]=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH:9]=[CH:10][C:11]=1[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH3:3].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH3:3][C:2]([OH:34])([C:4]#[C:5][C:6]1[CH:7]=[C:8]([C:21]2[CH:22]=[CH:23][C:24]([C@@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:29])[F:30])=[CH:25][CH:26]=2)[CH:9]=[CH:10][C:11]=1[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH3:1]
Reactant: CC(C)(O)C#Cc1cc(-c2ccc([C@@](C)(O)C(F)(F)F)cc2)ccc1S(=O)(=O)c1ccccc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC(C)(O)C#Cc1cc(-c2ccc([C@](C)(O)C(F)(F)F)cc2)ccc1S(=O)(=O)c1ccccc1

Procedure:
2-methyl-4-(4-(phenylsulfonyl)-4′-((1R)-2,2,2-trifluoro-1-hydroxy-1-methylethyl)-3-biphenylyl)-3-butyn-2-ol. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, J=8.2 Hz, 1H), 8.05 (d, J=7.8 Hz, 2H), 7.92-7.81 (m, 2H), 7.79-7.66 (m, 5H), 7.64-7.55 (m, 2H), 1.77 (s, 3H), 1.59 (s, 6H). m/z (ESI, +ve ion) 471.0 (M-OH)+. GK-GKRP EC50 (NADPH-coupled)=1.80 μM; GK-GKRP EC50 (LC MS/MS)=2.25 μM.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]([CH2:26][CH2:27][CH3:28])[S:19]([CH:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CCCI
Reactant: CC(C)S(=O)(=O)NCc1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCN(Cc1cccc(-c2cccc(S(C)(=O)=O)c2)c1)S(=O)(=O)C(C)C

Procedure:
In analogy to example 10, step 3, propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-amide was reacted with 1-iodopropane and cesium carbonate in N,N-dimethylacetamide to give propane-2-sulfonic acid (3′-methanesulfonyl-biphenyl-3-ylmethyl)-propyl-amide as a colorless, waxy solid. MS: 427.2 ([M+NH4]+)
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([CH3:18])=[N:11][C:12]([CH3:17])=[C:13]([Br:16])[C:14]=1O.P(Cl)(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[Br:8][C:9]1[C:10]([CH3:18])=[N:11][C:12]([CH3:17])=[C:13]([Br:16])[C:14]=1[Cl:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(C)c(Br)c(O)c1Br
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(C)c(Br)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Triethylamine (28.8 mL, 206 mmol) was added to a nitrogen purged solution of 3,5-dibromo-2,6-dimethylpyridin-4-ol (58 g, 206 mmol) and phosphorous oxychloride (57.7 mL, 619 mmol) in chloroform (450 mL) and stirred for 1 h at rt, then 3 h at 80° C. The reaction was removed from heating and immediately concentrated under house vaccum; then under high vacuum. The appearance was a cream colored solid, which was azeotroped with toluene (2×100 mL); treated with ice (200 g) for 10 min and carefully neutralized with NaHCO3 (powder), and 1N NaOH solution, and extracted with DCM (2×400 mL). The combined organic layers were dried (MgSO4), concentrated, and a beige solid was obtained that was washed with hexanes and dried under high vacuum to give 3,5-dibromo-4-chloro-2,6-dimethyl-pyridine 52.74 g (85.1%). Concentration of the hexanes gave 3.5 g of less pure product.