Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+].[OH-].[Na+].C(Cl)(Cl)Cl>CO>[OH:5][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[CH2:3][NH2:2]
Reactant: COc1ccc(C(=O)CN)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C(O)CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
2-Amino-4′-methoxyacetophenone hydrochloride (500 mg) was dissolved in methanol (10 ml), the solution was added with sodium borohydride (188 mg), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with sodium borohydride (188 mg), and further stirred for 30 minutes. The reaction mixture was added with 5 N aqueous sodium hydroxide (1 ml), the mixture was stirred for 10 minutes, and then added with chloroform, and the layers were separated. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and then the filtrate was concentrated under reduced pressure to obtain the title compound (240 mg).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:11](Cl)=[C:10]([C:13]([OH:15])=O)[CH:9]=[CH:8][N:7]=1.Cl.Cl.[CH3:18][NH:19][NH:20][CH3:21].CCN(C(C)C)C(C)C.C(N(CC)CC)C>C(Cl)Cl.O.CN1C(=O)CCC1.CN(C=O)C>[Cl:5][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:13](=[O:15])[N:20]([CH3:21])[N:19]([CH3:18])[C:11]=12
Reactant: O=C(O)c1ccnc(Cl)c1Cl
Reactant: CNNC
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)c2ccnc(Cl)c2n1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (92 μl, 1.25 mmol) is added to a mixture of 2,3-dichloro-pyridine-4-carboxylic acid (200 mg, 1.04 mmol), DCM (2 ml) and DMF (20 μl). The mixture is heated to 100° C. for 10 minutes in a microwave. The mixture is concentrated in vacuo. DCM (2.5 ml) and 1,2-dimethylhydrazine dihydrochloride (207 mg, 1.55 mmol) is added before DIPEA (1.35 ml, 7.77 mmol) in DCM (2.5 ml) is added dropwise at RT. Stirring is continued for 1 hour. The mixture is diluted with DCM and extracted with water. The combined organic layers are dried over Na2SO4 and concentrated in vacuo. NMP (1 ml) and triethylamine (200 μl, 1.5 mmol) is added and the mixture heated to 190° C. for 25 minutes in a microwave. At RT water is added (500 μl) and the product purified by RP HPLC. Yield: 50 mg (24%). HPLC-MS: M+H=198; tR=0.44 min (METHOD—1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:18]2[CH2:22][C@H:21]([CH2:23]OS(C)(=O)=O)[O:20][C:19]2=[O:29])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]1.[N-:30]=[N+:31]=[N-:32].[Na+]>CN(C=O)C>[N:30]([CH2:23][C@@H:21]1[O:20][C:19](=[O:29])[N:18]([C:4]2[CH:5]=[CH:6][C:7]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][F:16])[C:10](=[O:17])[CH2:9]3)=[C:2]([F:1])[CH:3]=2)[CH2:22]1)=[N+:31]=[N-:32]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CCN(CCF)C(=O)C3)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3CCN(CCF)C(=O)C3)c(F)c2)C(=O)O1
Temperature: 80 °C
Yield: 65.5 %

Procedure:
(5R)-3-(3-Fluoro-4-{4-(2-fluoroethyl)-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyl-oxymethyl)oxazolidin-2-one (719 mg) was dissolved in dry DMF (15 ml), and sodium azide (647 mg) added to the mixture. The mixture was heated at 80° C. for 6 hours, and then evaporated to dryness. The resulting residue was dissolved in ethyl acetate, washed twice with water, and dried (MgSO4). Evaporation gave (5R)-5-azidomethyl-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)oxazolidin-2-one (413 mg) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8](Cl)=[O:9])=[C:5]([CH3:7])[N:6]=1.[NH2:11][C:12]1[C:20]([NH:21][C:22]([C:24]2[CH:29]=[N:28][CH:27]=[CH:26][N:25]=2)=[O:23])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].O>N1C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:8]2[O:9][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:22]([C:24]4[CH:29]=[N:28][CH:27]=[CH:26][N:25]=4)=[O:23])[C:12]=3[N:11]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(C(=O)Cl)s1
Reactant: Nc1c(NC(=O)c2cnccn2)cccc1C(=O)O
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)o2)s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.3 %

Procedure:
2,4-dimethylthiazole-5-carbonyl chloride 17 (104 mg, 0.58 mmol) was added to a suspension of 2-amino-3-(pyrazine-2-carboxamido)benzoic acid 16 (100 mg, 0.39 mmol) in pyridine (5 mL). The reaction mixture was stirred at room temperature for 12 h then poured into ice cooled H2O (30 mL). The resulting precipitate was collected by filtration, rinsed with H2O, and dried under vacuum to give 18 (110 mg, 81% yield).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C:16]([O:47][CH3:48])([NH:17][C:18](=[O:46])[C:19](=[N:25][O:26]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(=O)(O)[O-].[Na+]>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@@:16]([NH:17][C:18](=[O:46])[C:19](=[N:25][OH:26])[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)([O:47][CH3:48])[C:15](=[O:49])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: COC1(NC(=O)C(=NOC(c2ccccc2)(c2ccccc2)c2ccccc2)c2cccs2)C(=O)N2C(C(=O)[O-])=C(COC(C)=O)CS[C@@H]21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@]1(NC(=O)C(=NO)c2cccs2)C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@@H]21
Reaction time: 0.17 h

Procedure:
t-Butyl (6R,7R and S [ca 1:8])-3-acetoxymethyl-7-methoxy-7[2-triphenylmethoxyimino-2-(thien-2-yl)-acetamido]-ceph-3-em-4-carboxylate (1.172 g, 1.56 mmole) was stirred with anisole (1.5 ml) and trifluoroacetic acid (5 ml) for 1 hour at +20°. The solution was added dropwise to vigorously stirred saturated aqueous sodium bicarbonate solution (400 ml); the mixture was stirred for 10 minutes and then washed with ethyl acetate (3×80 ml). The aqueous layer was covered with ethyl acetate (80 ml) and adjusted to pH 3 with orthophosphoric acid. The aqueous layer was extracted with ethyl acetate (3×80 ml) and the combined ethyl acetate layers were washed with brine, then passed through Whatman 1 PS phase-separating paper and evaporated. The residual foam was chromatographed on kieselgel G (60 g) in 4:1:5 butan-1-ol:ethanol:water. The appropriate fractions were combined and evaporated and the residue was dissolved in acetone, filtered through Celite, and evaporated to provide the title compound as a pale-brown amorphous solid containing 0.8 mole butan-1-ol, and 0.07 mole acetone (nmr) and 5 mole water (416 mg, 0.66 mole, 42.5%), paper chromatography Rf/Rf cephaloram 0.84, [α]D +40° (Me2SO), λmax (pH 6-buffer) 264.5 nm, inflexion at 290 nm (ε 15,200 and 10,700 respectively).
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:28][S:27](=[O:30])(=[O:29])[C:26]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:11]=3[N:12]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl.Cl[CH2:41][CH2:42][N:43]1[CH:47]=[CH:46][N:45]=[CH:44]1>CN(C=O)C.O>[N:43]1([CH2:42][CH2:41][O:20][C:16]2[CH:15]=[C:14]([N:12]3[C:11]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=5[S:27](=[O:29])(=[O:30])[CH2:28][C:10]=4[C:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])=[N:13]3)[CH:19]=[CH:18][CH:17]=2)[CH:47]=[CH:46][N:45]=[CH:44]1
Reactant: O=C(c1nn(-c2cccc(O)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: ClCCn1ccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1nn(-c2cccc(OCCn3ccnc3)c2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-[3-(morpholin-4-ylcarbonyl)-5,5-dioxidothiochromeno[4,3-c]pyrazol-1(4H)-yl]phenol (206.5 mg; 0.49 mmol; 1 eq.), potassium carbonate (401.6 mg; 2.91 mmol; 5.99 eq.) and sodium iodide (11.7 mg; 0.08 mmol; 0.16 eq.) in DMF (4 ml) is added N-(2-chloroethyl)-imidazole hydrochloride (158.4 mg; 0.95 mmol; 1.95 eq.). The suspension is stirred at 80° C. 2 days then in the microwave at 120° C. for 30 min. The reaction mixture is diluted with water and the product is extracted with EtOAc. The combined organic layer is washed with water then with brine, dried over MgSO4 and the solvent removed under vacuum to afford a brown residue. After purification by flask chromatography (silica; DCM/MeOH 98/2 to 0/100), it affords the title compound as a fluffy yellow powder. 1H NMR (DMSO-d6): δ 8.07-7.98 (m, 1H), 7.73-7.55 (m, 3H), 7.55-7.44 (m, 1H), 7.28-7.13 (m, 3H), 7.09-7.00 (m, 1H), 6.93-6.83 (m, 2H), 4.10 (s, 2H), 4.44-4.22 (m, 4H), 4.00-3.87 (m, 2H), 3.75-3.55 (m, 6H). HPLC (max plot) 93.5%; Rt 2.48 min. MS (ESI+): 520.4.
Reaction SMILES: ClC(Cl)(Cl)C(O)=[O:4].[CH3:8][O:9][C:10](=[O:22])[CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=1>CO.S(=O)(=O)(O)O.[Hg]=O>[CH3:8][O:9][C:10](=[O:22])[CH2:11][CH2:12][C:13](=[O:4])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Br:21])[N:16]=1
Reactant: COC(=O)CCC#Cc1cccc(Br)n1
Reactant: O=C(O)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: O=[Hg]
Solvent: CO
Product: COC(=O)CCC(=O)Cc1cccc(Br)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 35975.5 %

Procedure:
A mixture of 500 mg of red mercury oxide, 0.2 ml of boron trifluoride-diethyl ether complex and 10 mg of trichloroacetic acid in 1 ml of methanol is heated to 60° C. and a solution of 9.4 g of 5-(6-bromo-2-pyridyl)-4-pentynoic acid methyl ester in 15 ml 0f methanol is added to this catalyst solution at room temperature and the mixture is stirred for 2 hours at room temperature. Then, the reaction mixture is poured in 5% sulfuric acid, extracted with ethyl acetate, dried (Na2SO4) and concentrated by evaporation. 6.3 g of 5-(6-bromo-2-pyridyl)-4-oxo-pentanoic acid methyl ester is obtained as bright yellow oil.
Reaction SMILES: Br.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH2:4][C:3]1=[O:11].[H-].[Na+].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:35][CH3:36])=[C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:23]=2)[N:18]=[CH:17][N:16]=1>C1COCC1.CN(C=O)C>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]([C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:35][CH3:36])=[C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:23]=3)[N:18]=[CH:17][N:16]=2)[C:3]1=[O:11]
Reactant: O=C1Cc2cccnc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2ncnc(C3C(=O)Nc4ncccc43)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.9 %

Procedure:
7-Azaoxindole hydrobromide (269 mg, 1.25 mmol), (Tet.Let. 1987, 28, 4027), was added to a suspension of sodium hydride (100 mg, 2.5 mmol, prewashed with hexane) in a mixture of THF (3 ml) and DMF (3 ml). After stirring for 40 minutes at ambient temperature, 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline (169 mg, 0.5 mmol) was added. After heating for 1 hour at 75° C., the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and adjusted to pH8 with 2M hydrochloric acid. After extraction with methylene chloride, the organic layer was dried (MgSO4), filtered and the volatiles removed by evaporation. The residue was dissolved in methylene chloride/methanol and 3M hydrogen chloride in ether (0.5 ml) was added. After dilution with ether, the solid was collected by filtration and dried under vacuum to give 4-(7-azaoxindol-3-yl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline (150 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9]C(=O)C)=[CH:4][C:3]=1[Cl:13].[OH-].[Na+].O>C(O)CO>[Br:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[CH:4][C:3]=1[Cl:13]
Reactant: CC(=O)Nc1cc(Cl)c(Br)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1cc(Cl)c(Br)c(Cl)c1
Reaction time: 12 h

Procedure:
202 g of N-(4-bromo-3,5-dichlorophenyl)acetamide and 220 g of sodium hydroxide (as an aqueous 50% solution) in 670 ml of ethylene glycol are stirred for 5 hours at 120° C. and then for 12 hours at room temperature. 3000 ml of water are added, the mixture is filtered, the organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The residue obtained is crystallized from cyclohexane; m.p.=132° C.
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]1=[O:30])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[OH:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20]1=[O:30]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccccc2)C1=O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1[C@H](O)CCN1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3R)-3-(tert-butyldiphenylsilyloxy)-1-phenylpyrrolidin-2-one (2.88 g, 6.93 mmol) in THF (8.6 mL) at 0° C. was added TBAF (13.9 mL of 1 M in THF, 13.86 mmol) slowly and the reaction mixture was stirred at RT for 3 h. The reaction mixture was poured into water and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and evaporated to dryness. Purification by silica gel chromatography (0-10% MeOH in DCM) gave (R)-3-hydroxy-1-phenylpyrrolidin-2-one as a white solid (0.9 g 73%). 1H-NMR (400 MHz, DMSO-d6) δ 7.69 (d, J=7.8 Hz, 2H), 7.40-7.36 (m, 2H), 7.14 (t, J=7.4 Hz, 1H), 5.75 (d, J=5.8 Hz, 1H), 4.33-4.27 (m, 1H), 3.77-3.66 (m, 2H), 2.44-2.36 (m, 1H) and 1.86-1.81 (m, 1H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[N:2]1.[CH2:14](O)[CH3:15]>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:2]1
Reactant: O=C(O)Cc1n[nH]c2ccccc12
Reactant: CCO
Product: CCOC(=O)Cc1n[nH]c2ccccc12
Yield: 87.8 %

Procedure:
2-(1H-indazol-3-yl)acetic acid (3.9 g, 22.1 mmol) was dissolved in anhydrous ethanol (100 mL) concentrated sulfuric acid (5 mL), and heated under reflux for 16 hours. It was concentrated under reduce pressure to remove most of ethanol, then water (30 mL) was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated to obtain the product 3.96 g, at a yield of 87.8%.
Reaction SMILES: OC[N:3]1[C:7]2[N:8]=[C:9]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:10]=[C:11]([O:12][C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH:16]=[CH:17][CH:18]=3)[C:6]=2[CH:5]=[CH:4]1.N>CO>[CH3:37][N:34]1[CH2:33][CH2:32][N:31]([C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:9]3[N:10]=[C:11]([O:12][C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:23])[CH:21]=[CH2:22])[CH:16]=[CH:17][CH:18]=4)[C:6]4[CH:5]=[CH:4][NH:3][C:7]=4[N:8]=3)=[CH:30][CH:29]=2)[CH2:36][CH2:35]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3c2ccn3CO)c1
Agent: N
Solvent: CO
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of Compound 4 (100 mg, 0.2 mmol) in methanol (2 mL) was saturated with ammonia. The reaction mixture was stirred overnight at room temperature. Monitoring by LC-MS indicated that all starting material had been consumed. The solvent was concentrated and the crude material was purified by column chromatography (DCM/MeOH=20/1) to give Compound 1 (60 mg, yield 63.8%, M+H+=470.5) as a pale yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][CH:19]=1)[O:8][CH2:9][CH2:10][CH:11]1[O:16]CCCO1)([CH3:4])([CH3:3])[CH3:2].Cl>O1CCCC1.C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:17]([CH:11]([OH:16])[CH2:10][CH2:9][O:8]2)=[CH:18][CH:19]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cccc(OCCC2OCCCO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)c1ccc2c(c1)OCCC2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The intermediate from step A was dissolved in 20 ml tetrahydrofuran. Concentrated hydrochloric acid (20 mL) was added, and the reaction mixture was stirred at ambient temperature for 4 hours, diluted with diethyl ether and washed with water. The isolated organic layer was dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to give 2.87 g of crude 7-tert-butyl-chroman-4-ol which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:31][CH2:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:28]=5)[C:23]4=[O:39])=[CH:18][C:17]=3F)[CH2:12]2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)[C:43](O)=[O:44]>>[CH2:9]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C@@H:34]6[CH2:38][CH2:37][CH2:36][O:35]6)[CH:28]=5)[C:23]4=[O:39])=[CH:18][C:17]=3[O:44][CH3:43])[CH2:12]2)[CH2:11][NH:8]1
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc(N4CCc5cc(OC[C@@H]6CCCO6)ccc5C4=O)cc3F)C2)C1
Reactant: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCC2(CNC2)C1

Procedure:
Reaction of 6-(2-Fluoro-4-{1-oxo-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-phenyl)-2,6-diaza-spiro[3.4]octane-2-carboxylic acid tert-butyl ester with trifluoroacetic acid by method H2 resulted in the desired product with the molecular weight 451, 55 (C26H30FN3O3); MS (ESI): 452 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7](Br)[CH:6]=1)[CH3:2].[CH:14]([Zn]C(C)C)([CH3:16])[CH3:15]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([CH:14]([CH3:16])[CH3:15])[CH:6]=1)[CH3:2]
Reactant: CC(C)[Zn]C(C)C
Reactant: CCOC(=O)c1ccc(Cl)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(Cl)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-4-chlorobenzoic acid ethyl ester (1.05 g, 3.99 mmol) was added in one portion to a solution of diisopropylzinc (10.0 mmol, 1M toluene, Aldrich) in 10 mL of 1,4-dioxane followed by addition of Pd(dppf)2Cl2 (4.0 mmol). The mixture was heated to reflux 3 hours, cooled to ambient temperature and stirred overnight. The mixture was quenched with 1N aqueous HCl, diluted with ethyl acetate, and filtered through celite. The separated organic layer was washed sequentially with 1N aqueous HCl, brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by chromatography eluting with 4% ethyl acetate/hexanes to provide the title compound. 1H NMR (DMSO-d6) δ 7.92 (d, 1H), 7.78 (dd, 1H), 7.58 (d, 1H), 4.32 (q, 2H), 3.35 (sept, 1H), 1.32 (t, 3H), 1.24 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][C@@:3]([NH:9][C@H](C1C=CC=CC=1)CO)([CH3:8])[C:4]([F:7])([F:6])[F:5].CS(O)(=O)=O>CO.Cl.[OH-].[OH-].[Pd+2]>[F:5][C:4]([F:7])([F:6])[C@@:3]([CH3:8])([NH2:9])[CH2:2][NH2:1]
Reactant: C[C@@](CN)(N[C@@H](CO)c1ccccc1)C(F)(F)F
Agent: [Pd+2]
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CO
Product: C[C@](N)(CN)C(F)(F)F
Reaction time: 24 h
Yield: 45.2 %

Procedure:
A mixture of 10.50 g (70 mmol) of (R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenylethanol in methanol, 4.5 mL (68 mmol) of methanesulfonic acid and 1.50 g of Pd(OH)2/C (20% w/w) is hydrogenated at 25° C. in an autoclave, under a hydrogen pressure of 5 bar, for 24 hours. The mixture obtained is then filtered and the filtrate is evaporated to dryness. The oil obtained is taken up in 3 M hydrochloric acid solution (42 mL). The mixture obtained is extracted with ethyl ether. Ethyl ether and 15 mL of 35% sodium hydroxide are then added to the aqueous phase, to pH 12. The aqueous phase is then separated out by settling and extracted with 3 times 200 mL of ethyl ether. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated under vacuum to give 4.50 g of (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine in the form of a pale yellow oil, the characteristics of which are as follows:
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:23](=[O:38])[N:24]([CH3:37])[C@@H:25]([C:33](=[O:36])[NH:34][CH3:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:14]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:12][C:11]([CH2:10][C@@H:9]([NH:7][CH3:6])[C:23]([N:24]([CH3:37])[C@@H:25]([C:33](=[O:36])[NH:34][CH3:35])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:38])=[CH:16][CH:15]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
((1R)-2-(1,1′-Biphenyl-4-yl)-1-(methyl-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-carbamoyl)ethyl)methyl-carbamic acid tert-butylester (1.0 g; 1.8 mmol) was dissolved in methylene chloride (4 mL). Trifluoroacetic acid (4 mL) was added and the reaction mixture was stirred for 15 min at room temperature. Methylene chloride (40 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 40 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 9. The organic phase was dried (magnesium sulfate) and the solvent was removed in vacuo to afford 0.76 g of (2R)-3-(1,1′-biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:5]=1[C:6]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:7]>C(O)C>[Cl:3][C:4]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:5]=1[C:6]([O:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7]
Reactant: CCOC(=O)COC(=O)c1c(Cl)cccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
Potassium hydroxide, 0.8 gram (0.012 mole), was powdered and dissolved in 50 ml of ethanol. The solution was warmed to 40°-50° and 3.1 grams (0.011 mole) of (ethoxycarbonyl)methyl 2,6-dichlorobenzoate (the compound of Example IX) was added in portions during a 5-minute period. Upon completion of the addition a precipitate formed. The reaction mixture was stirred at ambient temperature for 18 hours. The potassium salt was collected by filtration, washed with ethanol, dried, placed in an Erlenmeyer flask, and stirred with 50 ml of water. To the resultant solution was added a solution of 10 ml of concentrated hydrochloric acid in 40 ml of water. The solid precipitate was collected by filtration and washed with water. The filter cake was dissolved in 100 ml of ethyl acetate and dried with sodium sulfate. The mixture was filtered and the filtrate evaporated under reduced pressure to give 1.1 grams of carboxymethyl 2,6-dichlorobenzoate; mp 180°-181.5°. The nmr and the ir spectra were consistent with the proposed structure.