Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:41])[O:5][CH2:6][CH:7]([NH:18][C:19](=[O:40])[CH2:20][N:21]1[C:25](=[O:26])[N:24](/[CH:27]=[CH:28]/[C:29]([F:32])([F:31])[F:30])[C:23]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)=[N:22]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:2]>CO.[Pt]>[CH2:1]([NH:3][C:4](=[O:41])[O:5][CH2:6][CH:7]([NH:18][C:19](=[O:40])[CH2:20][N:21]1[C:25](=[O:26])[N:24]([CH2:27][CH2:28][C:29]([F:32])([F:31])[F:30])[C:23]([C:33]2[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=2)=[N:22]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:2]
Reactant: CCNC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(/C=C/C(F)(F)F)c1=O)c1ccccc1C(F)(F)F
Agent: [Pt]
Solvent: CO
Product: CCNC(=O)OCC(NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(CCC(F)(F)F)c1=O)c1ccccc1C(F)(F)F

Procedure:
A solution of 168 mg (0.28 mmol) of the compound from Example 146 in 30 ml of methanol was hydrogenated by means of a continuous-flow hydrogenation apparatus (H-Cube, Thales Nano, Budapest, Model HC-2-SS), equipped with a 5% Pt/C catalyst cartridge, at 70° C. with a flow rate of 1 ml/min under standard pressure. The methanol was removed on a rotary evaporator and the residue was purified by preparative HPLC [Method 20]. This gave 96 mg (55% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]([OH:10])[C:7]([O:9][CH3:18])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)C(O)c1ccc(Br)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1ccc(Br)cc1

Procedure:
4-Bromomandelic acid, with sulfuric acid added thereto, is reacted in methanol, to give methyl 2-(4-bromophenyl)-2-hydroxyacetate.
Reaction SMILES: [CH:1](=[N:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16]Cl)[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:32].[Na+]>CC(C)=O>[CH:1](=[N:8][CH:9]1[C:30](=[O:31])[N:11]2[C:12]([C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:19])=[C:13]([CH2:16][I:32])[CH2:14][S:15][C@H:10]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(N=Cc4ccccc4)C(=O)N23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(CI)CS[C@@H]3C(N=Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
30 g (65.65 mM) of p-methoxybenzyl 7-benzylideneamino-3-chloromethyl-3-cephem-4-carboxylate was dissolved in 500 ml of acetone. Then, 29.5 g (197 mM) of sodium iodide was added thereto, and the mixture was stirred at room temperature for 1 hour. From the reaction solution thus obtained, the solvent was distilled off under reduced pressure. To the residue, 500 ml of ethyl acetate was added. The mixture was washed with a saturated sodium thiosulfate aqueous solution and then with a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 27 g (yield: 75%) of p-methoxybenzyl 7-benzylideneamino-3-iodomethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].C([Li])CCC.C(#N)C.[F:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C1COCC1.O>[NH2:22][C:21]([C:20]1[CH:23]=[CH:24][C:17]([F:16])=[CH:18][CH:19]=1)=[CH:2][C:1]#[N:4]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O
Product: N#CC=C(N)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A solution of 0.390 ml (2.78 mmol) diisopropylamine in dry THF (2 ml) was cooled to −70° C. under inert gas atmosphere, and 1.74 ml (2.78 mmol) n-butyllithium solution (1.6 M in hexanes) were added dropwise. Then, a solution of 129 μl (2.45 mmol) acetonitrile in dry THF (2 ml) was slowly added over 10 min. The resulting solution was stirred for further 30 min at −70° C. before a solution of 200 mg (1.635 mmol) 4-fluorobenzonitrile in dry THF (2 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 h before water (4 ml) was added slowly. The mixture was extracted several times with dichloromethane (50 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield 244 mg (92% of th.) of the crude title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([C@@H:19]5[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]5[N:15]4[CH2:14][CH2:13][CH2:12]3)[CH:18]=2)=[C:5]([C:25]([F:28])([F:27])[F:26])[CH:4]=1.[C:29](O)(=O)[CH3:30]>>[CH2:29]([N:23]1[CH2:22][CH2:21][C@@H:20]2[N:15]3[C:16]4[C:11](=[CH:10][C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=5[C:25]([F:28])([F:26])[F:27])=[CH:18][C:17]=4[C@@H:19]2[CH2:24]1)[CH2:12][CH2:13][CH2:14]3)[CH3:30]
Reactant: CC(=O)O
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c(C(F)(F)F)c1
Product: CCN1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(OC)cc3C(F)(F)F)cc3c1N2CCC3
Temperature: 55 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
To a solution of (7aS,11aR)-2-[4-methoxy-2-(trifluoromethyl)phenyl]-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.077 mmol) in acetic acid (0.28 mL) was added NaBH (30 mg, 0.80 mmol) in 2 portion in 10 min interval at 55° C. The reaction mixture was stirred for 15 h at 55° C. then quenched by addition of H2O. The aqueous solution was basified with 50% NaOH then extracted with CHCl3. The combined organic solution was dried over MgSO4, concentrated in vacuo. The residue was chromatographed (silica gel; CHCl3: MeOH 99:1–98:2) to give the title compound as a yellow oil (26 mg, 81%). 1H NMR (CDCl3, 300 MHz) δ 1.21–1.35 (m, 3H), 2.05–2.30 (m, 5H), 2.53–2.78 (m, 6H), 2.98–3.07 (br, 1H), 3.08–3.18 (br, 1H), 3.27–3.42 (m, 2H), 3.43–3.57 (br, 1H), 3.88 (s, 3H), 6.83 (s, 1H), 6.86 (s, 1H), 7.04 (dd, J=8.8, 2.9 Hz, 1H), 7.20–7.26 (m, 2H) ppm. MS (CI, NH3): 417.1 (base, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][N:36]([CH3:39])[C:35]1=[O:40]>O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][N:36]([CH3:39])[C:35]4=[O:40])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Reactant: CN1CCN(CCCl)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(CCN2CCN(C3Cc4cc(Cl)ccc4Sc4ccccc43)CC2)C1=O

Procedure:
8.3 g of 1-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 11.6 g of powdered potassium carbonate, 0.2 g of potassium iodide and 80 ml of toluene, with 8.6 g of β-chloroethyl-3-methyl-2-imidazolidinone and the mixture is heated under reflux for 20 hours. The mixture is then poured into water, the organic phase washed with water, dried over sodium sulphate and evaporated. There is obtained 1-[2-[4-(2-chloro-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-3-methyl-2-imidazolidinone as a brown oil. By treatment of this compound with maleic acid in ethanol/ether there is obtained the corresponding maleate which melts at 186°-188° C.
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.C1(C)C=CC=CC=1.C(OO)(=[O:26])C>O>[OH:26][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CC(=O)OO
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
While stirring a mixture of 22.5 g of ethyl 2-(4-formylphenoxy)propionate ([α]D25 =+51.5°) and 60 g of toluene at room temperature, 22.8 g of 40% peracetic acid was dropwise added. After stirring at 20° to 30° C. for 2 hours and at 50° C. for 2 hours, 0.2 g of water was added, and the mixture was stirred for 2 hours. After cooling the reaction mixture to room temperature, 40 g of water was added. The aqueous layer was separated. The organic layer was washed with 40 g of water, followed by washing twice with 40 g of a 5% sodium hydrogen carbonate aqueous solution, then with 40 g of a 5% sodium hydrogen sulfite aqueous solution and further with 40 g of water. Then, the reaction mixture was concentrated by distilling off toluene under reduced pressure, and subjected to distillation under reduced pressure, whereby 16.5 g of (+)-ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([F:28])=[CH:15][C:16]([F:27])=[C:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=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.C([O-])([O-])=O.[Cs+].[Cs+].[C:77]([NH2:80])(=[O:79])[CH3:78]>O1CCOCC1.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]>[C:77]([NH:80][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[C:14]([F:28])=[CH:15][C:16]([F:27])=[C:17]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:23])[CH3:24])[CH:18]=3)[C:8]([CH3:12])=[N:9]2)=[CH:4][N:3]=1)(=[O:79])[CH3:78]
Reactant: Cc1nc2cc(Cl)ncc2cc1-c1cc(NC(=O)OC(C)(C)C)c(F)cc1F
Reactant: CC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)Nc1cc2nc(C)c(-c3cc(NC(=O)OC(C)(C)C)c(F)cc3F)cc2cn1
Temperature: 100 °C
Yield: 89.9 %

Procedure:
Sparge a mixture of tert-butyl (5-(7-chloro-2-methyl-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)carbamate (0.664 g, 1.636 mmol), XantPhos (0.189 g, 0.327 mmol), Cs2CO3 (1.066 g, 3.27 mmol) and acetamide (0.483 g, 8.18 mmol) in dioxane (16 mL) with Ar, add Pd2(dba)3 (0.150 g, 0.164 mmol) and heat at 100° C. overnight. Cool to RT, remove the solids via filtration through diatomaceous earth, rinse well with THF, concentrate the filtrate to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (630 mg, 90%) as a glass. MS (ESI) m/z: 429.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])=[CH:4][C:3]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Cu][C:41]#[N:42]>CN1C(=O)CCC1>[O:33]([CH2:32][C:3]1[CH:4]=[C:5]([C:8]2([O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])[OH:9])[CH:6]=[CH:7][C:2]=1[C:41]#[N:42])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(=O)OC[C@H]1OC(O)(c2ccc(Br)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CC(=O)OC[C@H]1OC(O)(c2ccc(C#N)c(COc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Alternatively, the compound described above is synthesized starting from 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranos-1-yl)-2-(phenoxymethyl)-benzene using copper(I) cyanide (2 equivalents) in NMP at 210° C.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][NH2:26])[CH2:21][CH2:20]4)[CH:14]=3)[O:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.O>[C:2]1([CH:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@@H:19]4[CH2:24][CH2:23][C@H:22]([CH2:25][NH:26][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:21][CH2:20]4)[CH:14]=3)[O:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC[C@H]1CC[C@@H](Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)NC[C@H]1CC[C@@H](Oc2ccc3c(c2)CCC(c2ccccc2)O3)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
To a solution of 150 mg [cis-4-(2-phenyl-chroman-6-yloxy)-cyclohexylmethyl]amine hydrochloride (0.40 mmol) at room temperature in 4 ml of pyridine 47 μl of methanesulfonyl chloride (0.60 mmol) were added and stirring at room temperature was continued for 16 h. The reaction mixture was diluted with water and extracted with dichloromethane The combined organic layers were washed with diluted aqueous hydrochloric acid, dried with sodium sulfate and filtered, and the solvent removed under reduced pressure. The crude product was purified by reversed phase HPLC. 97 mg of the title compound were isolated as a white solid.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:11]=[CH:10]3)[N:5]=[C:4]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1.[C:27](Cl)([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28].C([O-])(O)=O.[Na+]>CCOC(C)=O>[C:23]([C:4]1[CH:3]=[C:2]([C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[N:11]=[CH:10]3)[N:5]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3N)ccc21
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1ncc2cc(-n3nc(C(C)(C)C)cc3C(=O)OCC(Cl)(Cl)Cl)ccc21
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirring suspension of tert-butyl 5-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (see WO 2006/071940A2, 0.250 g, 0.70 mmol) and Troc-Cl (0.10 ml, 0.74 mmol) in EtOAc (7 ml) at RT was added sat'd. NaHCO3 (2.9 ml, 2.1 mmol). After 3 h, the completed reaction was diluted with hexanes (35 ml) and filtered. The solid was rinsed well with hexanes and dried to afford tert-butyl 5-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.36 g, 97% yield). MS (ESI) m/z: 532.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:12]([O:13][CH3:14])[CH3:11])=[O:5]
Reactant: CNOC
Reactant: O=C(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.5 %

Procedure:
To a solution of 2-fluorobenzoyl chloride (50 g, 0.31 mol) in CH2Cl2 (200 mL) was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), and a solution of triethylamine (127 g, 1.26 mol) in CH2Cl2 (100 mL) at 0° C. The reaction mixture was warmed slowly to rt, and stirred for 3 h. The mixture was quenched with iced water and extracted with CH2Cl2 (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-fluoro-N-methoxy-N-methylbenzamide (48 g, yield: 84.6%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]1)=[O:11].Cl[C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[CH:22][C:21]([CH3:24])=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[N:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Reactant: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ccc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)nn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-pyrazol-1-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. ESI-MS (m/z): 473 [M+1]+.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[OH-].[Na+:18]>O>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O-:10])=[O:9])=[CH:5][CH:6]=1.[Na+:18]
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Biphenylacetic acid (25.0 g, 0.1177 mol.) and sodium hydroxide (4.71 g, 0.1177 mol.) were dissolved in 50 mL of water and stirred at room temperature for 2 hours. The product was isolated by evaporating off the water.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:29])[F:28])[CH:21]=2)=[CH:4][CH:3]=1.CS([O:37][CH2:38][C:39]1([CH2:42]O)[CH2:41][CH2:40]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:42][C:39]4([CH2:38][OH:37])[CH2:41][CH2:40]4)[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]([F:30])([F:28])[F:29])[CH:21]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)OCC1(CO)CC1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC2(CO)CC2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (80 mg, 0.17 mmol, intermediate 9) in DMF (5 mL) was added (1-(hydroxymethyl)cyclopropyl)methyl methanesulfonate (0.1 g, 0.5 mmol, intermediate 42), potassium carbonate (47 mg, 0.34 mmol) and TBAI (2 mg, 0.02 mmol). The reaction was stirred at 50° C. for 8 h. The mixture was cooled and partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-3-methyl-8-(3(trifluoromethoxy)phenoxy)-1H-purine-2,6(3H,7H)-dione (36 mg, 39.9% yield) as a white solid. 1H-NMR (CD3OD) δ 7.39(t, 1H), 7.01(dd, 1 H), 6.88-6.90(m, 2H), 4.87-4.88(m, 2H), 4.44-4.46(m, 2H), 4.08-4.16(m, 4H), 3.61(t, 2H), 3.51(s, 3H), 1.80-1.90(m, 2H), 1.32(t, 3H). LCMS retention time 3.099 min; LCMS MH+ 533.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[NH:32]C(=O)OC(C)(C)C)=[O:24])=[CH:21][CH:20]=2)=[N:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)[CH:8]=1)#[N:2].Cl.O>C(OCC)(=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([C:4]2[C:3]([C:1]#[N:2])=[CH:8][C:7]([CH2:9][N:10]3[CH2:15][CH2:14][N:13]([CH:16]([CH3:17])[CH3:18])[CH2:12][CH2:11]3)=[CH:6][N:5]=2)=[CH:41][CH:40]=1
Reactant: CC(C)N1CCN(Cc2cnc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)c(C#N)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)N1CCN(Cc2cnc(-c3ccc(C(=O)Nc4ccccc4N)cc3)c(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
t-Butyl {2-[(4-{3-cyano-5-[(4-isopropylpiperazin-1-yl)methyl]pyridin-2-yl}benzoyl)amino]phenyl}carbamate (586 mg, 1.06 mmol; prepared as described in Method 19) was dissolved in ethyl acetate (7 ml) and 3M aqueous hydrochloric acid (7 ml) was added. The resulting suspension was stirred for 6 hours at ambient temperature then 3M aqueous hydrochloric acid (1.75 ml) added. The suspension was stirred for a further 2 hours then 3M aqueous hydrochloric acid (3.5 ml) was added and stirred for 30 minutes. The suspension was poured into water (50 ml) and washed with ethyl acetate (3×15 ml). The resulting aqueous solution was basified using a 2M aqueous solution of sodium hydroxide. A pale yellow precipitate crashed out which was filtered and washed with water. The pale yellow solid was dried in a vacuum oven at 50° C. ovenight (294 mg, 62%); NMR Spectrum: (CDCl3) 0.99 (d, 6H), 2.48 (m, 8H), 2.60 (m, 1H) 3.56 (s, 2H), 3.79 (br s, 2H), 6.80 (m, 2H), 7.03 (m, 1H), 7.32 (d, 1H), 7.81 (br s, 1H), 7.99 (s, 4H), 8.04 (s, 1H), 8.74 (s, 1H); Mass Spectrum: M+H+ 455.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[OH-].[Na+].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][C:16](=[O:18])[NH:15][C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@]1(NC(=O)OCc2ccccc2)CC(=O)NC1=O
Yield: 48 %

Procedure:
5.0 g of 2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide were dissolved in 100 g of dimethylsulfoxide and thereto, 100 g of 0.05 mol/L citrate buffer solution (pH 4.4) were added, followed by adjusting pH value of the resultant mixture to 6.5 with a 5% sodium hydroxide aqueous solution. Thereto, 0.28 mL of esterase (PLE (2.7 kU/mL); manufactured by BioCatalytics, Inc., ammonium sulfate suspension) were added and the resultant mixture was stirred at 25° C. for 78 hours, followed by analyzing quantitatively the reaction mixture. As a result, in the reaction mixture, 2.4 g (quantitative yield: 48.6%) of (R)-2-benzyloxycarbonylamino-2-ethoxycarbonyl succinimide having an optical purity of 97-5% e.e. were contained
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[P:6](=[O:14])([N:11]=[C:12]=[O:13])([S:9][CH3:10])[O:7][CH3:8]>CCOCC>[S:1]1[CH2:5][CH2:4][N:3]([C:12]([NH:11][P:6](=[O:14])([S:9][CH3:10])[O:7][CH3:8])=[O:13])[CH2:2]1
Reactant: C1CSCN1
Reactant: COP(=O)(N=C=O)SC
Solvent: CCOCC
Product: COP(=O)(NC(=O)N1CCSC1)SC
Temperature: 25 °C

Procedure:
A solution of 4.45 g of thiazolidine in 100 ml of ether was cooled to about 0° C. and 8.35 g of O,S-dimethyl phosphoroisocyanatidothioate was added dropwise with stirring. The mixture was allowed to warm to ambient temperature and react for about 1 hour at which time the precipitate that formed was collected by filtration. This precipitate was then recrystallized from a small amount of 2-propanol to obtain 3.6 g (28 percent of theory) of the title compound as white crystals melting at 84°-86° C.
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][C:4]=2[C:3]=1[Br:16].Cl.N([O-])=O.[Na+].[PH2](=O)O>C1COCC1.O>[Br:16][C:3]1[C:4]2[CH:5]=[CH:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:2]=1
Reactant: Nc1ccc2c(ccc3ccccc32)c1Br
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: C1CCOC1
Solvent: O
Product: Brc1cccc2c1ccc1ccccc12
Reaction time: 1 h
Yield: 66.1 %

Procedure:
First, 120 g of 2-amino-1-bromophenanthrene were dissolved in 750 mL of THF, and then 4.5 L of concentrated hydrochloric acid and 1.5 L of water were added to the solution. The reaction solution was cooled with ice, and then a solution of 45 g of sodium nitrite in 230 mL of water was dropped to the solution. After the mixture had been stirred for 1 hour under ice cooling, 2.25 L of a 50% aqueous solution of phosphinic acid were added to the mixture. The reaction solution was stirred for 30 minutes under ice cooling, and was then continuously stirred at room temperature for 17 hours. Subsequently, 10 L of water were added to the solution, and a solid was obtained through separation by filtration. The resultant solid was purified by silica gel column chromatography. Thus, 75 g of 1-bromophenanthrene were obtained (in 66% yield).