Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([NH:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:35]=[CH:34][C:33]([N:36]([CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH3:1])=[CH:32][CH:31]=4)[CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: CCOC(=O)CCCNc1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1
Reactant: C1CCOC1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CCCN(C)c1ccc(N2CCN(C(=O)c3cccc(-c4ccc(OC)c(OC)c4)n3)CC2)cc1

Procedure:
To a THF solution of ethyl 4-[N-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)amino]butanoate were added a 36% aqueous formalin solution, acetic acid and sodium triacetoxyborohydride, followed by stirring. Then, post-treatment and purification were carried out in a usual way to obtain ethyl 4-[N-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenyl)-N-methylamino]butanoate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.BrC1C=CC(OC2C=CC=CC=2)=C(Cl)C=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1O
Reactant: OB(O)c1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Clc1cc(Br)ccc1Oc1ccccc1
Solvent: CC#N
Product: Cc1cc(Br)ccc1Oc1ccccc1
Yield: 35 %

Procedure:
The title compound was prepared in a 35% yield from 4-bromo-2-methylphenol and phenyl boronic acid in a manner similar to that described for the preparation of 4-bromo-2-chloro-1-phenoxybenzene: 1H NMR (DMSO-d6, 400 MHz) δ 7.54(s, 1H), 7.35(m, 3H), 7.12(t, 1H), 6.93(d, 2H), 6.82(d, 2H), 2.18(s, 3H); RP-HPLC (Hypersil HS, 5 μm, 100 A, 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 mmin) tr 14.25min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]3[CH2:22][C:21]([CH3:24])([CH3:23])[NH:20][C:19]([CH3:26])([CH3:25])[CH2:18]3)=[CH:12][CH:11]=2)=[C:4]([F:28])[CH:3]=1.Cl.N1C=CC=CC=1>CO.CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:28])[C:5]([C:10]2[N:15]=[N:14][C:13]([N:16]([CH3:27])[CH:17]3[CH2:18][C:19]([CH3:25])([CH3:26])[NH:20][C:21]([CH3:24])([CH3:23])[CH2:22]3)=[CH:12][CH:11]=2)=[C:6]([OH:8])[CH:7]=1
Reactant: COc1cc(Br)cc(F)c1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: Cl
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: CN(c1ccc(-c2c(O)cc(Br)cc2F)nn1)C1CC(C)(C)NC(C)(C)C1
Yield: 24.1 %

Procedure:
6-(4-Bromo-2-fluoro-6-methoxyphenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (0.81 g, 1.80 mmol) and pyridine hydrochloride (1.65 g, 14.3 mmol) were heated to 190° C. for 45 min in a Biotage® Initiator microwave reactor. The reaction mixture was diluted in MeOH/DMSO, and purified via reverse phase preparative HPLC (5 to 95% acetonitrile in water, 0.1% trifluoroacetic acid as modifier). The appropriate fractions containing product were free based by catch and release using SiliaBond Propylsulphonic Acid® (4 eq, methanol as eluent and a 2 N ammonia solution in MeOH to release the material). The solvent was concentrated in vacuo to afford 5-bromo-3-fluoro-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol as a beige solid (0.19 g, 23%). [M+H]: 439.2; 1H NMR (400 MHz, MeOD) δ 7.96 (d, J=10.0 Hz, 1H), 7.27 (d, J=10.0 Hz, 1H), 6.97 (t, J=2.0 Hz, 1H), 6.89 (dd, J=11.5, 2.0 Hz, 1H), 5.07-5.35 (m, 1H), 3.02 (s, 3H), 1.73 (dd, J=12.5, 3.5 Hz, 2H), 1.62 (t, J=12.5 Hz, 2H), 1.41 (s, 6H), 1.27 (s, 6H).
Reaction SMILES: C([O:8][CH2:9][CH:10]1[N:15]2[C:16](=[O:22])[CH:17]=[C:18]([OH:21])[C:19]([OH:20])=[C:14]2[C:13](=[O:23])[N:12]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:11]1)C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH:10]1[N:15]2[C:16](=[O:22])[CH:17]=[C:18]([OH:21])[C:19]([OH:20])=[C:14]2[C:13](=[O:23])[N:12]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:11]1
Reactant: O=C1c2c(O)c(O)cc(=O)n2C(COCc2ccccc2)CN1Cc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: O=C1c2c(O)c(O)cc(=O)n2C(CO)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-[(benzyloxy)methyl]-2-(4-fluorobenzyl)-8,9-dihydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione (151 mg) and 5% Pd/C (57 mg) in ethanol (20 mL) was stirred under an atmosphere of hydrogen (1 atm) at room temperature overnight. The product mixture was filtered through a pad of Celite, and concentrated under vacuum. The residue was subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provided the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].S([O-])([O-])(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:45][C:46]1[CH:51]=[C:50]([O:52][CH2:53][CH:54]=[C:55]([Cl:57])[Cl:56])[CH:49]=[C:48]([Cl:58])[C:47]=1[OH:59].[OH-].[Na+].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O>[Cl:45][C:46]1[CH:51]=[C:50]([O:52][CH2:53][CH:54]=[C:55]([Cl:57])[Cl:56])[CH:49]=[C:48]([Cl:58])[C:47]=1[O:59][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: OCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
A mixture of 0.53 g of 3-bromopropanol, 5.0 g of toluene and 0.06 g of tetra-n-butylammonium sulfate was heated to 60° C. Thereto was added dropwise a mixed solution of 1.0 g of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of water and 0.54 g of a 27% aqueous sodium hydroxide solution with stirring over 6 hours. After completion of the addition, the mixture was further stirred at 60° C. for 4 hours. Then 0.10 g of 3-bromopropanol and 0.10 g of a 27% aqueous sodium hydroxide solution were added thereto, and the mixture was further stirred for 10 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution and 4.3 g of toluene were added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.2 q of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 89%, yield: 91%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH:22]1(B(O)O)[CH2:24][CH2:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]3[CH2:24][CH2:23]3)[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1C1CC1

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 200 mg), cyclopropylboronic acid (100 mg), potassium phosphate (410 mg) and tetrakis(triphenylphosphine)palladium(0) (65 mg) in dioxane (5 mL) was heated under reflux for 23 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and filtered through a column of porous diatomite (Chem Elut), and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (114 mg) as a colorless viscous oil.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23](OCC)=[O:24])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[OH:24][CH2:23][C:5]1[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]2[C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(-c2ccccc2)c2c3ccccc3ccn2c1C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1c(CO)c(-c2ccccc2)c2c3ccccc3ccn12
Reaction time: 5 h
Yield: 92.5 %

Procedure:
A solution of ethyl 3-isopropyl-1-phenylpyrrolo-[2,1-a]isoquinoline-2-carboxylate (6.25 g) in anhydrous diethyl ether (100 ml) was added to a stirred suspension of lithium aluminum hydride (2.7 g) in diethyl ether (160 ml) at -2° C. under an atmosphere of argon. The mixture was stirred at between -5° and 0° C. for 5 hours and then the reaction mixture was quenched by the dropwise addition of ethyl acetate (50 ml), followed by dilute hydrochloric acid (100 ml; 1N), maintaining the temperature below 10° C. The organic phase was then separated. The aqueous phase was extracted with dichloromethane (2×150 ml) and the organic solutions were combined, washed with brine (300 ml), dried over magnesium sulphate and evaporated, to give 2-hydroxymethyl-3-isopropyl-1-phenylpyrrolo[2,1-a]-isoquinoline (5.1 g) in the form of a sticky yellow solid. [N.M.R. (in DMSO-d6): 1.48 (6H, d, J= 7 Hz), 3.65 (1H, septet, J=7 Hz), 4.3 (2H, d, J=4 Hz), 4.5 (1H, broad t, J=4 Hz), 6.85 (1H, d, J=8 Hz), 7.0-7.7 (9H, m), and 8.1 (1H, d, J=8 Hz)].
Reaction SMILES: COC1C=CC(O)=CC=1.BrCCCCCCCCCO.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:25][CH:24]=1.COC1C=CC(OCCCCCCCCC(O)=O)=CC=1.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:26]1[CH:38]=[CH:39][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1ccc(OCCCCCCCCCO)cc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: COc1ccc(O)cc1
Agent: COc1ccc(OCCCCCCCCC(=O)O)cc1
Agent: Cl
Product: COc1ccc(OCCCCCCCCC(=O)N[C@H](CC(=O)OCc2ccccc2)CN(C)C)cc1

Procedure:
The title compound, m/e=409.5 ([M+H]+), was produced in analogy with example 18, steps 1 to 4. Thus, 4-methoxy-phenol was alkylated in step 1 with 9-bromo-1-nonanol, leading to 9-(4-methoxy-phenoxy)-nonan-1-ol, which was oxidized in step 2 to 9-(4-methoxy-phenoxy)-nonanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-[9-(4-methoxy-phenoxy)-nonanoylamino]-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26][CH2:27][CH:28]2[N:31]([CH2:32][C:33]([OH:35])=[O:34])[C:30](=[O:36])[CH:29]2[NH:37][C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1>CCOCC.O1CCOCC1>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([O:26][CH2:27][C@H:28]2[N:31]([CH2:32][C:33]([O:35][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:34])[C:30](=[O:36])[C@H:29]2[NH:37][C:38]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:25])=[O:24])=[CH:21][CH:22]=1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2CC(=O)O)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2[C@H](NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2CC(=O)OC(c2ccccc2)c2ccccc2)cc1
Temperature: 20 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A solution of 2.68 g of diphenyldiazomethane in 59 ml of ether was added to a solution of 6.55 g of 4-{[(4-methylphenyl)-sulfonyloxy]-methyl}-3-(triphenylmethylamino)-2-oxo-azetidin-1-yl-acetic acid in 70 ml of dioxane and after stirring for 3 hours at 20° C. 448 mg of diphenyldiazomethane were added. The mixture was stirred at 20° C. for 16 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica and was eluted with a 10-0.5 methylene chloride-ether mixture to obtain 7.5 g of diphenylmethyl racemic cis 4-{[(4-methylphenyl)-sulfonyloxy]-methyl)-3-triphenylmethylamino-2-oxo-azetidin-1-yl-acetate.
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=O)=[O:15])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[Cl:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=1[NH:61][CH:62]1[CH2:67][CH2:66][N:65]([C:18](=[O:20])[CH2:17][NH:16][C:14](=[O:15])[C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:13][CH:12]=2)[CH2:64][CH2:63]1
Reactant: Clc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(Nc2ccccc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Cl)CC1)c1ccc(Nc2ccccc2)nc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a stirred solution of [(6-phenylamino-pyridine-3-carbonyl)-amino]-acetic acid (0.035 g, 0.00013 mol) in DMF (1 mL) was added DIPEA (0.05 g, 0.00039 mol), HOBt (0.0209 g, 0.00015 mol) and EDCI.HCl (0.029 g, 0.00015 mol) at ambient temperature. After 2 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.0382 g, 0.00015 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.051 g (85%) of N-{2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-6-phenylamino-nicotinamide. LCMS: 464.18 (M+1)+, 98.3%, 1H NMR (DMSO-d6): δ 9.4 (s, 1H), 8.7 (d, 1H), 8.4 (t, 1H), 8.0 (d, 1H), 7.7 (d, 2H), 7.3 (m, 3H), 7.15 (t, 1H), 7.0 (t, 1H), 6.85 (d, 2H), 6.4 (t, 1H), 4.9 (d, 1H), 4.35 (d, 1H), 4.1 (d, 2H), 3.9 (d, 1H), 3.6 (s, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (t, 2H), 1.5 (m, 1H), 1.4 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[OH:9])#[N:2].[Br:20]N1C(=O)CCC1=O>C(#N)C>[Br:20][C:7]1[CH:6]=[C:5]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][N:19]=2)[C:13]([O:15][CH3:16])=[O:14])[CH:4]=[C:3]([C:1]#[N:2])[C:8]=1[OH:9]
Reactant: COC(=O)c1ccnc(-c2ccc(O)c(C#N)c2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COC(=O)c1ccnc(-c2cc(Br)c(O)c(C#N)c2)c1

Procedure:
Methyl 2-(3-cyano-4-hydroxyphenyl)isonicotinate and N-bromosuccinimide were stirred at room temperature in acetonitrile to obtain methyl 2-(3-bromo-5-cyano-4-hydroxyphenyl)isonicotinate. FN: 333.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23](=[O:33])[N:24]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:25])=[CH:11][N:10]=1)(C)(C)C.[ClH:35]>CCOC(C)=O>[ClH:35].[CH2:26]([N:24]([CH3:25])[C:23]([C:12]1[C:13]2[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=1)=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1cc2c(C(=O)N(C)Cc3ccccc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(C(=O)N(C)Cc3ccccc3)cnc(CN)c2cc1OC
Yield: 79 %

Procedure:
As described in example 1, a solution of [4-(benzyl-methyl-carbamoyl)-6,7-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (82 mg) was treated with HCl in EtOAc to give 56 mg (79%) of 1-aminomethyl-6,7-dimethoxy-isoquinoline-4-carboxylic acid benzyl-methyl-amide hydrochloride: 1H NMR (DMSO-d6) δ 2.68 (s, 2H), 3.67 (s, 2H), 3.91 (s, 1H), 3.97 (s, 3H), 4.33 (br s, 1H), 4.67-4.72 (m, 3H), 6.80 (s, 1H), 7.04-7.51 (m, 6H), 8.36 (d, 1H, J=4.26 Hz), 8.56-8.63 (m, 3H); MS: APCI (M+H) calc'd for C21H23N3O3 366.2; found 366.1.
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH:3]([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:1][CH:2]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH:3]([CH3:5])[CH3:4]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)C(C)N
Solvent: C1CCOC1
Product: CC(C)C(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1,2-dimethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 mL) was slowly added a solution of 1,3-propane sultone (13.7 g, 110 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with THF (50 mL) and EtOH (50 mL). The resulting solid was dried in vacuo, to afford compound DQ (17.5 g, 76%). 1H NMR (D2O, 500 MHz) δ ppm 3.07 (m, 3H), 2.88 (t, 2H, J=7.3 Hz), 1.97 (m, 3H) 1.10 (d, 3H, J=6.8 Hz), 0.85 (d, 3H, J=6.8 Hz), 0.81 (d, 3H, J=6.8 Hz). 13C NMR (D2O, 125 MHz) δ ppm 59.79, 48.19, 44.18, 29.72, 21.51, 18.44, 15.02, 10.71. ES-MS 232 (M+Na).
Reaction SMILES: [CH:1]([SiH:4]([CH:13]([CH3:15])[CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Cl:16]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.Cl[SiH3]>C(Cl)Cl>[Cl:16][Si:4]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)([CH:1]([CH3:3])[CH3:2])[CH:13]([CH3:15])[CH3:14]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: COc1ccc([SiH](C(C)C)C(C)C)cc1
Agent: [SiH3]Cl
Solvent: ClCCl
Product: COc1ccc([Si](Cl)(C(C)C)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Diisopropyl(4-methoxyphenyl)silane (47.7 g, 214 mmol, 1.0 equiv.), was taken up in CH2Cl2 (700 mL). The solution was cooled to 0° C. and trichloroisocyanuric acid (16.6 g, 71.3 mmol, 0.33 equiv.) was carefully added in three equal portions, making sure that each portion has at least 7 min to react before the next is added (caution: adding trichloroisocyanuric acid too rapidly results in a rapid evolution of gas). The mixture was stirred at 0° C. for 40 min followed by warming to 23° C. with stirring. The solids were filtered under an inert atmosphere and the filtrate concentrated in vacuo to yield 54.8 g (98%) of a cloudy oil. The chlorosilane, which is unstable, was used immediately and without purification in the next step.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25]([C@@:27]3([OH:39])[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:38])([CH3:37])[CH2:28]3)=[N:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25]([C@@:27]3([OH:39])[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:37])([CH3:38])[CH2:28]3)=[N:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:10]=1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN=[N+]=[N-])cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
To a solution of the product from Step 2 (220 mg, 0.392 mmol) in THF (4 ml) and water (2 ml), was added resin-bound triphenylphosphine (154 mg, 0.588 mmol, 1.5 equiv). The resulting mixture was stirred at 23° C. for 18 h. The resin-bound triphenylphosphine was removed by filtration, and the residual biphasic, orange-maroon mixture was partitioned between EtOAc (45 ml) and water (55 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude orange oil was purified via reverse-phase HPLC (acetonitrile/water gradient with 0.1% TFA present). The TFA salt was converted to the free base by partitioning between EtOAc (55 ml) and saturated aqueous NaHCO3 (45 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The organic layer was filtered and concentrated, yielding methyl(1S,4R)-4-{5-[3-(aminomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (55 mg, 25%), as an orange oil. MS ESI: [M+H]+ m/z 536.2
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:9]([OH:10])[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:37](O)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[C@H:9]([O:10][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:8][CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: O=C(O)c1ccccc1
Reactant: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1[C@H](OC(=O)c2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 7A (13.5 g, 55 mmol) in anhydrous THF (500 mL) was added triphenylphosphine (26 g, 99 mmol), followed by benzoic acid (10.1 g, 82.7 mmol) and DEAD (9.5 mL, 60 mmol). The reaction mixture was stirred at RT for 2 hours, then partitioned between water and CH2Cl2. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with 15% EtOAc/hexane to give 18.1 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].C(O[C:18]1[C:22]([NH2:23])=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[S:20](=[O:29])(=[O:28])[N:19]=1)C>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[C:22]([NH2:23])=[C:21]([S:24]([CH3:27])(=[O:25])=[O:26])[S:20](=[O:29])(=[O:28])[N:19]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CCOC1=NS(=O)(=O)C(S(C)(=O)=O)=C1N
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)C(S(C)(=O)=O)=C2N)o1
Reaction time: 15 h

Procedure:
To a solution of 2-[(5-dimethylaminomethyl-2furanyl)methylthio]ethylamine (0.66 g, 3.08 mmol) in acetonitrile (5 ml) under a nitrogen atmosphere there was added solid 3-ethoxy-4-amino-5-methylsulfonylisothiazole-1,1-dioxide (0.77 g, 3.01 mmol) to give an immediate solution and exothermic reaction. After 1/4 hour, the product began to crystallize and after stirring for 15 hours, was collected by filtration (1.2 g). The title compound was recrystallized by dissolving in hot methanol and diluting with several volumes of ether (1.0 g), mp 187°-189°.