Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@H:7]1[C@@H:12]([NH2:13])[CH2:11][CH:10]=[CH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH2:2]([O:4][C:5]([CH:7]1[CH:12]([NH:13][CH2:32][C:31]2[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=2)[CH2:11][CH:10]=[CH:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: CCOC(=O)[C@@H]1CC=CC[C@@H]1N
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC=CCC1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
cis-6-Amino-cyclohex-3-enecarboxylic acid ethyl ester hydrochloride (411.4 mg, 2 mmol) and anhydrous tetrahydrofuran (20 mL) were mixed to form slurry. Triethylamine (295 μL, 2.1 mmol), magnesium sulfate (685 mg), and 4-fluoro-benzaldehyde (450 μL, 4.1 mmol) were added at 25° C. and the resulted mixture was stirred at 25° C. for 16 h. The precipitated solid was filtered off and the filtrate was concentrated in vacuo at 25° C. to give an oil. This oil was dissolved in methanol (35 mL) and sodium borohydride (155 mg, 4.1 mmol) was then added portionwise at 25° C. The mixture was stirred at 25° C. for 1 h. Saturated aqueous sodium bicarbonate solution (15 mL) was added, extracted with ethyl acetate (3×40 mL) and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the desired product, 6-(4-fluoro-benzylamino)-cyclohex-3-enecarboxylic acid ethyl ester (537.6 mg, 1.94 mmol, 96.9%). This crude product was directly used in next step without further purification. LC-MS (ESI) calcd for C16H20FNO2 277.2, found 278.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([O:25][CH3:26])[CH:19]=2.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[CH3:26][O:25][C:20]1[CH:19]=[C:18]2[C:23]([CH:24]=[C:15]([C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:16]=[N:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2cc(Br)cnc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1

Procedure:
Followed Step 1 of Compound IV-1, starting from 4-(methoxycarbonyl)phenylboronic acid and Intermediate 13, and where the base used was Na2CO3, the solvent DME/H2O (8:2), and the reaction was run at 100° C. for 2 h.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([S:20]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=2)[N:8]=1)=O.[N:29]1[C:38]2[C:33](=[C:34]([NH:39][NH2:40])[CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[CH2:24]([N:23]([CH2:26][CH3:27])[S:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:39]([C:34]4[CH:35]=[CH:36][CH:37]=[C:38]5[C:33]=4[CH:32]=[CH:31][CH:30]=[N:29]5)[N:40]=[CH:3][CH:4]=3)=[N:8]2)[CH:15]=1)(=[O:22])=[O:21])[CH3:25]
Reactant: NNc1cccc2ncccc12
Reactant: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: CCN(CC)S(=O)(=O)c1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ncccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-N,N-diethyl-benzenesulfonamide (A-21) and quinolin-5-yl-hydrazine according to the method described for example 91. MS: M=501.2 (M+H)+
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:17]([C:13]1[CH:12]=[C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:16]=[CH:15][N:14]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH3:35]
Reactant: CCOC(=O)CCCCCCBr
Reactant: c1ccc(COc2ccnc(Nc3ccccn3)c2)cc1
Agent: O=S([O-])([O-])=S
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
NaH (245 mg, 6.38 mmol) was added to II (1.77 g, 6.38 mmol) in DMF (25 mL) at rt. After 15 min, KI (1.588 g, 9.57 mmol) and ethyl 7-bromoheptanoate (1.86 mL, 9.57 mmol) were added, and the reaction mixture was stirred at 90° C. for 17 h. Aqueous 0.1 M Na2S2O3 (100 mL) and EtOAc (100 mL) were added and the phases were separated. The organic phase was washed with brine (100 mL), dried over MgSO4, filtered, and subsequently evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography eluting with hexane/EtOAc (90:10 to 70:30) to furnish III as a yellow oil (1.321 g, 48%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[N:4][C:3]=1[C:8]1[CH:17]=[CH:16][C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=1.O1CCCC1.CCCCCC.C([Li])CCC.[C:34](=[O:36])=[O:35]>O>[CH3:7][C:5]1[O:6][C:2]([C:34]([OH:36])=[O:35])=[C:3]([C:8]2[CH:17]=[CH:16][C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[CH:9]=2)[N:4]=1
Reactant: Cc1nc(-c2ccc3c(c2)CCCC3)c(Br)o1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc3c(c2)CCCC3)c(C(=O)O)o1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a mixed solution of 5-bromo-2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole (11.0 g) and tetrahydrofuran (100 mL) was added dropwise a 1.6N n-butyllithium hexane solution (24 mL) at −78° C. under a nitrogen atmosphere. After stirring the reaction mixture at −78° C. for 10 min, CO2 gas was blown into the reaction mixture for 30 min. The reaction mixture was poured into water and washed with ether. The aqueous layer was acidified with conc. hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give [2-methyl-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-5-oxazolyl]carboxylic acid (7.4 g, yield 76%) as crystals. Recrystallization from ethyl acetate gave colorless crystals. melting point: 183–185° C.
Reaction SMILES: S(=O)(=O)(O)O.Cl.[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH2:17])[CH2:14]2.[OH-:18].[Na+]>[N+]([O-])(O)=O>[OH:18][C:13]12[CH2:15][CH:9]3[CH2:10][CH:11]([CH2:16][CH:7]([CH:8]3[NH2:17])[CH2:14]1)[CH2:12]2
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: [OH-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: NC1C2CC3CC1CC(O)(C3)C2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a mixture of concentrated sulfuric acid (300 ml) and concentrated nitric acid (30 ml) cooled in an ice bath to 10° C. is added tricyclo[3.3.1.13,7 ]decan-2-amine hydrochloride (20 g; 0.107 mole) in 5 g portions over 10 minutes. This mixture is then stirred for 2 hours with cooling. The reaction mixture is poured over ice and the pH raised to pH 10-11 using 40% NaOH. This mixture is extracted with chloroform, dried over MgSO4 and evaporated to dryness to give 5-hydroxytricyclo[3.3.1.13,7 ]decan-2-amine as a solid residue (m.p. 267°-270° C.) which is used directly in step B.
Reaction SMILES: [NH:1]1[C:11]2[C:12]3[C:3]([CH2:4][NH:5][CH2:6][C:7]=3[CH:8]=[CH:9][CH:10]=2)=[CH:2]1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][C:23](Cl)=[O:24].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:20][CH2:21][CH2:22][C:23]([N:5]1[CH2:4][C:3]2=[CH:2][NH:1][C:11]3[C:12]2=[C:7]([CH:8]=[CH:9][CH:10]=3)[CH2:6]1)=[O:24]
Reactant: O=C(Cl)CCCl
Reactant: c1cc2c3c(c[nH]c3c1)CNC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CCCl)N1Cc2cccc3[nH]cc(c23)C1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline (3.24 g), described in Example 5, in chloroform (350 ml), triethylamine (6.0 ml) is added, followed by dropwise addition of 3-chloropropionyl chloride (4.2 ml). The mixture is stirred at room temperature for 2.5 hr. Aqueous sodium bicarbonate is added and the stirring is continued for 15 minutes. The layers are separated and the organic phase washed with water, dried and concentrated to give 4-(3-chloropropionyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinoline, mp 158°-161°C after recrystallizaton from chloroform.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH2:21][CH2:22][C:23](OCC)=[O:24])[C:5]2[O:9][CH2:8][CH:7]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:6]=2[C:19]=1[CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH2:21][CH2:22][CH2:23][OH:24])[C:5]2[O:9][CH2:8][CH:7]([C:10]3[CH:11]=[CH:12][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:15]=3)[C:6]=2[C:19]=1[CH3:20]
Reactant: CCOC(=O)CCc1c(C)c(N)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N)c(C)c2c(c1CCCO)OCC2c1ccc(C(C)C)cc1
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a suspension of ethyl 3-(5-amino-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate synthesized in Reference Example 321 (1.28 g, 3.36 mmol) in THF, was added Lithium aluminum hydride (255 mg, 6.72 mmol) at 0° C., and the mixture was stirred at the same temperature for 30 minutes and heated under reflux for 30 minutes. To the reaction solution was added water, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate to obtain 750 mg (yield 66%) of the title compound. Melting point: 110-111° C. (hexane-ethyl acetate).
Reaction SMILES: C([CH:3](O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])=[CH:8][CH:7]=1)C.N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:43][C:44]1[CH:49]=[CH:48][C:47]([S:50]([NH:53][C@@H:54]([C@H:61]([NH2:68])[C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:52])=[O:51])=[CH:46][CH:45]=1.CCN(CC)CC>C(Cl)Cl>[CH2:13]([O:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][NH:68][C@H:61]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C@H:54]([NH:53][S:50]([C:47]2[CH:46]=[CH:45][C:44]([CH3:43])=[CH:49][CH:48]=2)(=[O:52])=[O:51])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[CH:11][CH:10]=1)[CH2:14][CH2:15][CH2:16][C:17]#[CH:18]
Reactant: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Reactant: C#CCCCCOc1ccc(CCC(O)CC)cc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCCCOc1ccc(CCCN[C@H](c2ccccc2)[C@H](NS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Yield: 81.8 %

Procedure:
This compound was prepared according to general procedure 5 using 3 ethyl-3-(4-(hex-5-ynyloxy)phenyl)propan-1-ol (400 mg, 1.72 mmol), 2,6-lutidine (353 mg, 3.30 mmol), trifluoromethanesulfonic anhydride (787 mg, 2.80 mmol), (R,R)-TsDPEN (403 mg, 1.10 mmol), Et3N (263 mg, 2.60 mmol) and DCM (8 cm3). The product was purified by column chromatography as in the general procedure. TLC: silica gel, 30% EtOAc in petroleum ether, product Rf=0.36 with visualisation by UV and KMnO4, 2,6-lutidine Rf=0.29 with visualisation by UV, 2,6-lutidine elutes with the product). The fractions containing the product were collected, combined and dried under reduced pressure to give a white solid. The solid was then washed with pentane to remove residual 2,6-lutidine. The mixture was filtered and the solid dried to give the product as a white solid (524 mg, 0.900 mmol, 82% based on 403 mg, 1.1 mmol N-(2-aminoethyl)-4-methylbenzenesulfonamide)). Mp 123-124° C.; [α]D27−25.2 (c 0.25 in CHCl3) (R,R); (found (ESI): M++H, 581.2833 C36H41N2O3S requires M, 581.2832); υmax 3286, 3248, 2915, 1510, 1454, 1434, 1316, 1242, 1160, 1031, 808, 700 cm−1; δH (400 MHz, CDCl3) 7.37 (2H, d, J 8.5 Hz, CHArSO2), 7.13-7.11 (3H, m, CHAr), 7.05-6.88 (12H, m, CHAr and NHSO2 overlapping), 6.78 (2H, d, J 8.5 Hz, CHArSO2), 6.28 (1H, br s, NH), 4.25 (1H, d, J 7.8 Hz, CHNSO2), 3.95 (2H, t, J 5.0 Hz, CH2OAr), 3.59 (1H, d, J 7.8 Hz, CHN), 2.51-2.38 (3H, m, ArCH2 and CH2N overlapping), 2.31 (3H, s, CH3), 2.29-2.24 (3H, m, HCCCH2 and CH2N overlapping), 1.96 (1H, t, J 2.6 Hz, HCCCH2), 1.92-1.85 (2H, m, CH2CH2CH2OAr), 1.75-1.61 (4H, m, CH2CH2N and HCCCH2CH2); δC (100 MHz, CDCl3) 157.20 (CAr), 142.70 (CAr), 139.33 (CAr), 138.39 (CAr), 137.09 (CAr), 133.79 (CAr), 129.21 (2 CHAr), 129.10 (2 CHAr), 128.31 (2 CHAr), 127.93 (2 CHAr), 127.58 (2 CHAr), 127.46 (CHAr), 127.41 (2 CHAr), 127.29 (CHAr), 127.13 (2 CHAr), 114.39 (2 CHAr) 84.18 (C), 68.64 (CH), 67.77 (CH), 67.29 (CH2), 63.09 (CH), 46.45 (CH2), 32.37 (CH2), 31.71 (CH2), 28.37 (CH2), 25.11 (CH2), 21.46 (CH3), 18.19 (CH2); m/z (ESI) 581.3 (M++1).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=1[CH3:19])=[O:10])[NH:2]2.[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26](O)=[O:27])[N:25]=1>>[CH3:20][C:21]1[S:22][C:23]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:24]([C:26]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:27])[N:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3c(C)nc4sccn34)C[C@@H]3C[C@@H]32)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid. LC-MS (basic): tR=1.33 min; [M+H]+=492.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:13]([NH:16][C:17]3[C:22]([F:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=3)=[N:12][NH:11][C:10]=2[C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C1COCC1>[F:23][C:22]1[C:17]([NH:16][C:13]2[C:14]3[CH2:15][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([CH3:26])([CH3:25])[C:10]=3[NH:11][N:12]=2)=[N:18][C:19]([CH3:27])=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1Cc2c(Nc3nc(Cl)ncc3F)n[nH]c2C1(C)C
Reactant: CB1OB(C)OB(C)O1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncc(F)c(Nc2n[nH]c3c2CN(C(=O)OC(C)(C)C)C3(C)C)n1
Temperature: 100 °C

Procedure:
To a pressure vessel was added 3-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-6,6-dimethyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (1.50 g, 3.90 mmol), trimethylboroxine (10.9 mL, 78.4 mmol), cesium carbonate (25.5 g, 78.4 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.480 g, 0.588 mmol), H2O (6 mL), and THF (60 mL). The suspension was purged with argon for 2 min, then heat at 100° C. for 15 h. The cooled solution was filtered to remove undissolved solids. Purification by silica gel column chromatography using 0-10% ammoniated methanol in CH2Cl2 provided the desired product H1(i) as a brown solid (0.80 g, 56%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.41 (s, 9H) 1.57 (s, 6H) 2.38 (s, 3H) 4.43-4.58 (m, 2H) 8.12 (s, 1H) 10.02 (s, 1H) 12.34 (s, 1H). Mass Spectrum: Calcd for C17H24N6O2F (M+H): 363. Found: 363.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:45]1[CH:44]=[CH:43][C:42]([CH:39]2[CH2:38][CH2:37][N:36]([CH3:34])[CH2:41][CH2:40]2)=[CH:47][CH:46]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 25.2 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (250 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (32 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1COCC1.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]>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]2[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)C1CC1
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: Clc1nccc(C2CC2)n1
Temperature: 90 °C

Procedure:
Nitrogen gas was bubbled through a mixture of 2,4-dichloropyrimidine (1.49 g, 10 mmol), cyclopropaneboronic acid (0.86 g, 10 mmol) and K3PO4 (5.31 g, 25 mmol) in THF (50 ml) for 10 min. Pd(dppf)Cl2 (817 mg, 1 mmol) was added and the mixture heated at 90° C. in a sealed tube overnight. The mixture was cooled and partitioned between water and EtOAc, the organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by MPLC (Biotage Horizon: FLASH 25+M) eluent: 100% Hexanes (90 ml), gradient rising from 100% Hexanes to 20% EtOAc in Hexanes (900 ml), then 20% EtOAc in Hexanes (500 ml) to give 750 mg (48%) as an off-white solid. 1H NMR (CDCl3): 1.18 (m, 4H), 1.99 (m, 1H), 7.09 (d, J 5.1 Hz, 1H), 8.36 (d, J 5.1 Hz, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1>>[O:15]=[S:12]1(=[O:16])[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][N:11]1[CH2:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=3)[N:25]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(=O)(=O)CC1
Product: O=S1(=O)CCNCCN1Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 144 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 454. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.36 (s, 1H) 8.30 (d, 1H) 8.20 (d, 1H) 7.73 (d, 1H) 7.64 (t 1H) 7.53 (d, 1H) 7.14 (d, 2H) 6.68 (d, 2H) 4.70 (s, 2H) 3.80 (t, 2H) 3.67 (m, 4H) 3.56 (t, 2H) 3.36 (t, 2H) 2.95 (t, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>ClCCl>[CH:16]1([C:22]([C:13]2[S:12][C:11]([C:3]3[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:10])[F:9])[O:5][N:4]=3)=[CH:15][CH:14]=2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Product: Cc1c(-c2ccc(C(=O)C3CCCCC3)s2)noc1C(F)(F)F
Yield: 35 %

Procedure:
A solution of 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole (Preparative Example 21, 468 mg, 2.0 mmol) in dichloromethane (20 mL) was treated with FeCl3 (324 mg, 2.0 mmol) followed by cyclohexylcarbonyl chloride (268 μL, 05. mmol). The reaction was heated at reflux for 20 hours followed by evaporation and partitioning between EtOAc (25 mL) and an aqueous 1N hydrochloric acid solution (25 mL). The organic portion was then washed with a second portion of 1N hydrochloric acid solution and brine, dried over MgSO4, filtered, and concentrated in vacuo to afford crude product. The crude product was then chromatographed on silica gel with EtOAc/hexanes (3%) as eluant to afford product as a colorless solid (240 mg, 35%). 1H NMR (CDCl3) 1.24-1.76 (m, 6 H), 1.84-1.94 (m, 4 H), 2.37 (d, J=1.3, 3 H), 3.05-3.15 (m, 1 H), 7.54 (d, J=4.0, 1 H), 7.74 (d, J=4.0, 1 H). 13C NMR 7.9, 25.9, 26.0, 29.7, 47.8, 114.8, 118.7 (q, J=271), 129.1, 131.6, 135.5, 146.0, 155.4 (q, J=41), 158.0, 196.8. 19F NMR −63.1. LC/MS 7.92 min, [M+1]+ 344.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](Cl)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].O.O.O.O.O.O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21

Procedure:
A mixture of 1-ethyl-6-fluoro-7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (22g) and piperazine hexahydrate (160g) was heated at 135°-145° C. in an autoclave for 18.5 hr. The mixture was evaporated to dryness and dissolved in 10% sodium hydroxide. The solution was neutralized with acetic acid. The precipitate was collected, washed with water, dissolved in 30% acetic acid, and filtered. The filtrate was neutralized with 10% sodium hydroxide. The resulting precipitate was collected, washed with water and ethanol, and dried at 140°-145° C. in vacuo for 1.5 hr. to give 14g (54%) of 1-ethyl-6-fluoro-1,4-dihydro-7-(1-piperazinyl)-4-oxoquinoline-3-carboxylic acid (II) as colorless powder, m.p. 227°-228° C.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[CH2:17]1[CH2:24][O:23][S:20](=[O:22])(=[O:21])[CH2:19][CH2:18]1>>[CH3:16][N:2]([CH3:1])[S:3]([C:6]1[CH:15]=[CH:14][C:9]2[N+:10]([CH2:24][CH2:17][CH2:18][CH2:19][S:20]([O-:23])(=[O:22])=[O:21])=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: Cc1nc2ccc(S(=O)(=O)N(C)C)cc2s1
Reactant: O=S1(=O)CCCCO1
Product: Cc1sc2cc(S(=O)(=O)N(C)C)ccc2[n+]1CCCCS(=O)(=O)[O-]
Temperature: 160 °C
Yield: 91.2 %

Procedure:
A mixture of Compound 24 (2.55 g, 10.0 mmol) from step (a) of Example 27 and 1-4-butane sultone (2.98 g, 21.9 mmol) was heated in a pressure tube at 160° C. for 17 hours. The mixture was allowed to cool to room temperature, and the resulting mass was triturated with ethyl acetate (40 ml) until a pink solid separated. The solid was collected by centrifugation, washed with ethyl acetate and dried under vacuum to yield 3.58 g (92%) of Compound 26 with the structure:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9](Cl)[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21]>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[N:8]=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Product: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)nc(Cl)n1
Yield: 90 %

Procedure:
The title compound was prepared in analogy to examples described in WO 01/85700 A2 (Janssen Pharmaceutica) from 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (commercially available) and 2,4-dichloro-phenol in 90% yield. MS (ISP): 335.0 [M+H]+.