Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: C1COCCN1
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCOCC1

Procedure:
[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid prepared in Example 4 and morpholine were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:7]=[C:6]([O:8][CH3:9])[S:5][C:4]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])[CH:36]=[CH:37][CH:38]=[C:39]([CH:41]=O)[CH3:40])[CH3:31].C1OCCC1>C1(C)C=CC=CC=1>[CH2:30]([O:32][C:33](=[O:44])[CH:34]=[C:35]([CH3:43])/[CH:36]=[CH:37]/[CH:38]=[C:39]([CH3:41])[CH:40]=[CH:10][C:4]1[S:5][C:6]([O:8][CH3:9])=[CH:7][C:3]=1[CH3:2])[CH3:31]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: COc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)/C=C/C=C(C)C=Cc1sc(OC)cc1C

Procedure:
A suspension of 5.9 g. (13.5 mmol) of (3-methyl-5-methoxy-2-thenyl)triphenyl phosphonium chloride and 2.81 g. (13.5 mmol) of ethyl-7-formyl-3-mehtyl-2,4,6-octatrienoate in 70 ml. of butylene oxide and 200 ml. of toluene was heated to 100° C. for 14 hrs. The resulting clear solution was cooled, poured into 500 ml. of a methanol/water mixture (6:4) and extracted with hexane. The combined hexane extracts were washed with methanol/water (6:4), dried and evaporated. The resulting crude, oily material was purified by chromatography (silica gel, hexane/ether, ratio 7:3) to yield after recrystallization from hexane all trans-3,7-dimethyl-9-(3-methyl-5-methoxy-2-thienyl)-2,4,6,8-nonatetraenoic acid ethyl ester, m.p. 66°-72° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:11]=[C:10]([NH2:12])[CH:9]=[N:8][C:7]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[Br:19]N1C(=O)CCC1=O>CS(C)=O.O>[Br:19][C:9]1[C:10]([NH2:12])=[N:11][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:7]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: Nc1cnc(-c2ccncc2)c(-c2ccco2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: Nc1nc(-c2ccco2)c(-c2ccncc2)nc1Br
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.1 %

Procedure:
To a 0° C. stirred solution of 6-(2-furyl)-5-pyridin-4-ylpyrazin-2-amine (Example 5, 195 mg, 0.82 mmol) in dimethylsulfoxide (1.5 mL) and water (40 μL), was added portionwise N-bromosuccinimide (146 mg, 0.82 mmol). The mixture was stirred at room temperature for 40 min, then poured into water, extracted with dichloromethane (×3), the organic layers washed with brine, dried (MgSO4) and evaporated to furnish the title compound (198 mg, 75%) as a brown solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[K+].[N+](C1C=CC(S(O[C:18]2[CH2:19][C@@H:20]3[CH2:34][C:33](=[O:35])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])(=O)=O)=CC=1)([O-])=O>C(OCC)C>[N:1]([C:18]1[CH2:19][C@@H:20]2[CH2:34][C:33](=[O:35])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=[N+:2]=[N-:3]
Reactant: O=C(OCc1ccccc1)C1=C(OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C[C@@H]2CC(=O)N12
Reactant: [N-]=[N+]=[N-]
Agent: [K+]
Solvent: CCOCC
Product: [N-]=[N+]=NC1=C(C(=O)OCc2ccccc2)N2C(=O)C[C@H]2C1
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
Potassium azide (3.2 mg, 39 micromol) was added to a stirred, 0° C. solution of benzyl 2-(p-nitrobenzenesulfonyloxy)-carbapen-2-em-3-carboxylate (5.1 mg, 12 micromol) in anhydrous 5:1 (v/v) acetonitriledichloromethane. After 10 min. the mixture was applied to one 10 cm×20 cm 250 micron silica gel thin layer chromatography plate and developed with diethyl ether. The band centered at Rf 0.5 was eluted with ethyl acetate and the eluate was evaporated under vacuum to provide 1.2 mg (37%) benzyl 2-azidocarbapen-2-em-3-carboxylate.
Reaction SMILES: C([BH3-])#N.[Na+].[F:5][CH:6]([F:17])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[CH:11][NH:12]2>FC(F)(F)C(O)=O>[F:17][CH:6]([F:5])[O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][NH:12]2
Reactant: FC(F)Oc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: FC(F)Oc1cccc2c1CCN2
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.7 %

Procedure:
0.722 mg of sodium cyanoborohydride is added to a solution of 1 g of 4-difluoromethoxy-1H-indole in 15 ml of trifluoroacetic acid, cooled to 0° C., and the stirring is continued for 3 hours. The reaction mixture is then concentrated under reduced pressure, treated with a concentrated sodium hydroxide solution, extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of heptane and ethyl acetate (20/80: v/v), so as to give 300 mg of 4-difluoromethoxy-2,3-dihydro-1H-indole in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[C:15]([C:22](O)=[O:23])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:25]1([NH2:28])[CH2:27][CH2:26]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[CH:25]1([NH:28][C:22]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[O:23])[CH2:27][CH2:26]1
Reactant: NC1CC1
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2-c2cccs2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2-c2cccs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 1-{4-[(ethylamino)carbonyl]phenyl}-5-(2-thienyl)-1H-1,2,3-triazole-4-carboxylic acid (764 mg) obtained in Example 336a) in DMF (5 ml) were sequentially added cyclopropylamine (0.23 ml), triethylamine (0.46 ml), HOBt (170 mg) and WSC (640 mg), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=4/6 to ethyl acetate) and recrystallized from ethyl acetate to give the title compound as a colorless powder (543 mg, 64%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:15][N:16]1[CH2:21][CH2:20][C:19]([CH2:22]O)=[CH:18][CH2:17]1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:14])=[C:10]([O:13][CH2:22][C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN1CC=C(CO)CC1
Reactant: CC(=O)N1CCc2cc(Br)c(O)cc21
Product: CC(=O)N1CCc2cc(Br)c(OCC3=CCN(C)CC3)cc21

Procedure:
The title compound was prepared from 1-acetyl-5-bromo-6-hydroxyindoline (D64) and 1-methyl-1,2,5,6-tetrahydropyridine-4-methanol (J. Med. Chem., 1988, 31, 545) using the procedure of Description 8a in WO96/19477. The product was purified by acid/base extraction, then used in the next step.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:26]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[CH3:26][N:13]([CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]1[S:9][C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[N:12][CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)C(=CN(C)c1cnc(CN2CCOCC2)s1)C(=O)OCC
Temperature: 75 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a mixture of diethyl 2-(((2-(morpholin-4-ylmethyl)-1,3-thiazol-5-yl)amino)-methylene)malonate (Preparation 28, 1.51 g) and K2CO3 (1.19 g) in DMF (15 mL) at ambient temperature is added iodomethane (0.28 mL). The mixture is heated to 75° C. in a sealed pressure tube and stirred overnight. The solution is cooled to ambient temperature and the solvent is removed. The mixture is diluted with water (75 mL) and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed to afford 0.984 g (63%) of the title compound as a light brown solid. Physical characteristics: 1H NMR (CDCl3) δ1.24-1.33, 2.60, 3.31, 3.74, 4.17-4.24, 7.60; IR (liq.) 1702, 1608, 1535, 1453, 1383, 1365, 1293, 1270, 1232, 1206, 1117, 1096, 1071, 1010, 865 cm−1; HRMS (FAB) m/z 384.1600 (C17H25N3O5S+H). Anal. Found: C, 53.18; H, 6.64; N, 10.41.
Reaction SMILES: Cl[C:2]1[C:3]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[C:4]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[C:5](=[O:20])[N:6]([CH2:8][C:9]2[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[N:7]=1.O.[NH2:35][NH2:36]>>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:3]2[C:2]([NH:35][NH2:36])=[N:7][N:6]([CH2:8][C:9]3[C:10]([CH3:19])=[N:11][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:13][CH:14]=3)[C:5](=[O:20])[C:4]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:28][CH:29]=1
Reactant: NN
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc(Cl)c(-c2ccc(Cl)cc2)c(-c2ccncc2)c1=O
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(NN)c(-c2ccc(Cl)cc2)c(-c2ccncc2)c1=O
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a round bottom flask was added 6-chloro-5-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one (900 mg, 1.833 mmol), 1-BuOH (2 ml) and hydrazine hydrate (5 ml). The reaction was heated to 130° C. and stirred at that temperature for 8 hrs. After this time the reaction was cooled to rt and concentrated under reduced pressure. The reaction was poured into a separatory funnel and partitioned between EtOAc (50 ml) and water (20 ml). The layers were separated and the organic layer was washed with water (20 ml) and saturated aqueous NaCl (20 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the product 5-(4-chlorophenyl)-6-hydrazinyl-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-4-(pyridin-4-yl)pyridazin-3(2H)-one as yellow solid. HPLC retention time (method A) 1.138 min; LCMS (M+H)=487.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]1([C@@H:28]2[CH2:30][C@H:29]2[C:31](O)=[O:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:31]([C@@H:29]3[CH2:30][C@H:28]3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:32])[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NN=Cc2c(-c3ccccc3)[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc1c23
Yield: 28 %

Procedure:
Preparation of example 61 from the title compound of Example 7 (198 mg, 0.72 mmol), (1R,2R)-2-phenylcyclopropanecarboxylic acid (175 mg, 1.08 mmol; as described by. A. Thurkauf, et al., J. Med. Chem. 43, 3923-3932, (2000)), triethylamine (0.401 mL, 2.88 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (411 mg, 1.08 mmol) in N,N-dimethylformamide (10.0 mL) was carried out analogously to Example 11. Silica gel chromatography (3% methanol in CH2Cl2), also in an analogous manner, followed by collection on a frit and subsequent washing with diethyl ether afforded the title compound (86 mg, 0.20 mmol) as a yellow powder in 28% yield.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)=[N+]=[N-].[H][H]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH:13]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1
Reactant: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Cc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nc(CN)n(C)c1C(c1ccccc1)c1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 110 %

Procedure:
In 8 ml of ethanol was dissolved 150 mg (0.44 mmol)of 2-azidomethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (60), and 50 mg of 10% palladium carbon was added at -20° C. The mixture was stirred at room temperature under a stream of hydrogen. After 4 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated to give 94 mg of Compound I-101 (yield 68%).
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCOCC.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>N1C=CC=CC=1>[CH:22]1([C:25]([O:16][CH2:15][CH2:14][S:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:26])[CH2:24][CH2:23]1
Reactant: O=C(Cl)C1CC1
Reactant: CCCCCCCCCCCCSCCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCSCCOC(=O)C1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2.0 g. 2-hydroxyethyl dodecyl sulfide, 60 ml. anhydrous ether and 1.27 g. cyclopropyl carboxylic acid chloride at 0° is added 1.3 ml. pyridine. The mixture is allowed to warm to room temperature and is stirred for three days. The product is isolated using the procedure of Example 3 to yield 3-thiapentadecyl cyclopropanecarboxylate, boiling point 131° -137°137° (0.03 mm.).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(Cc2ccccc2)c1
Yield: 94.6 %

Procedure:
A mixture of ethyl 1-benzyl-1H-pyrazole-4-carboxylate (53.0 g, 0.23 mol) and LiOH (19.4 g, 0.46 mol) in THF (100 mL) and H2O (100 mL) was stirred at refluxed for 6 h. Then, THF was removed, the residue was acidify by 6 N HCl, precipitation was formed, filtered and dried to give the desired compound as a white solid (44.0 g, 92.8%). 1H NMR (DMSO-d6) δ 12.36 (s, 1H), 8.39 (s, 1H), 7.85 (s, 1H), 7.38-7.27 (m, 5H), 5.37 (s, 2H). MS (ESI) m/e [M+1]+ 202.9.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].N([O-])=O.[Na+].C([O-])([O-])=O.[Na+].[Na+].[ClH:20]>>[Cl:20][C@@H:2]([C@@H:3]([CH3:4])[CH2:5][CH3:6])[C:7]([OH:9])=[O:8]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Product: CC[C@H](C)[C@H](Cl)C(=O)O
Yield: 70 %

Procedure:
To a cooled (0° C.) solution of L-Isoleucine (40 g) dissolved in HCl (5N, 750 ml) was added dropwise a solution of sodium nitrite (35 g in 100 ml water). The reaction was stirred overnight at room temperature (˜23° C.), Na2CO3 (31 g) slowly added and the reaction mixture extracted with EtOAc (3×150 ml). The combined organic extracts washed with water, half saturated brine, dried over MgSO4, filtered and concentrated. The product a yellowish oil was distilled under reduced pressure (5 torr, bp=111° C.) to afford a colorless oil (32 g) obtained in 70% yield. (see FIG. 6).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH2:21])[CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>O1CCOCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:20]=[C:19]([NH:21][C:27](=[O:28])[C:26]3[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:25]=3[Cl:24])[CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(Oc2cccc(N)n2)CCN1Cc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Product: CC1(C)CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.5 %

Procedure:
Combine 6-(1-benzyl-2,2-dimethyl-piperidin-4-yloxy)-pyridin-2-ylamine (preparation 66, 0.537 g, 1.72 mmol), 1,4-dioxane (20 mL) and 2-chloro-4-fluoro-benzoyl chloride (0.20 g, 1.04 mmol), stir and heat to reflux. After 1.5 hr., cool to ambient temperature and concentrate. Dissolve the residue in methanol (10 mL) and load on an SCX column (10 g); wash with methanol (2×50 mL); elute product with 2M ammonia/methanol (2×50 mL). Concentrate the eluent. Purify the crude mixture by silica gel flash chromatography eluting with 9:1 hexane:ethyl acetate to obtain the title compound (0.056 g 11.5%). Mass spectrum (electrospray): m/z=468.2 (M+1); 1H NMR (CDCl3): 8.3 (bs, 1H), 7.8 (m, 2H), 7.6 (dd, 1H), 7.3 (m, 6H), 7.1 (m, 1H), 6.5 (d, 1H), 5.1 (m, 1H), 3.9 (d, 1H), 3.2 (d, 1H), 2.65 (m, 1H), 2.4 (m, 1H), 2.0 (m, 2H), 1.7 (m, 1H), 1.6 (m, 1H), 1.3 (s, 3H), 1.2 (s, 3H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:24][CH2:25][C:26](Cl)=O)[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].O=P(Cl)(Cl)Cl>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:24][CH2:25][C:26]1[O:11][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[N:12][N:13]=1
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(CCC(=O)Cl)cc1OC
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(CCc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol), TEA (0.153 ml; 1.1 mmol), 3,4-dimethoxyphenylpropionylchloride (228 mg, 1.1 mmol) and POCl3 (0.5 ml; 5.5 mmol) as described in method 1; yield: 0.019 mg (5.4%); MS m/z: 351.3 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.04 (t, 2H, 3J=7.5 Hz); 3.23 (t, 2H, 3J=7.5 Hz); 3.69 (s, 6H); 6.78 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 6.84 (d, 1H, 3J=8.3 Hz); 6.90 (d, 1H, 4J=1.7 Hz); 7.76 (d, 1H, 3J=8.3 Hz); 7.83 (dd, 1H, 4J=1.7 Hz, 3J=8.3 Hz); 8.17 (br s, 1H), 8.40 (s, 1H); HPLC (METHOD [A]): rt 10.29 min (94.2%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][CH2:45][NH2:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][CH:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCCC1CCN
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN1CCCC1CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 2-(1-methyl-pyrrolidin-2-yl)-ethylamine according to conditions described in general procedure C. Mp: 100-101° C., 1H NMR (400 MHz, DMSO-d6) δ 1.33-2.17 (m, 12 H), 2.88 (s, 2 H), 3.26 (t, J=4.4 Hz, 4 H), 3.77 (t, J=4.8 Hz, 4 H), 6.17-6.32 (bd, 1 H), 7.02-7.06 (m, 1 H), 7.12 (s, 1 H), 7.27 (d, J=8.7 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.61 (m, 3H), 7.82 (d, J=8.4 Hz, 1 H), 7.99 (d, J=7.7 Hz, 1 H), 8.23 (s, 1 H), 10.46 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.CCOCC>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([Br:22])[C:15]2[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(Br)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Yield: 18.5 %

Procedure:
A solution of (8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (501.9 mg, 1.717 mmol) and N-bromosuccinimide (366.0 mg, 2.056 mmol) in N,N-dimethylformamide (5 mL) was stirred at r.t. for 60 min. It was poured into 50 ml ether, washed with 5% aq. NaHCO3 two times, then with water 3 times, white precipitate formed, which was filtered and washed with ether to give 118 mg of the pure title product. Supernatant gave 490 mg more of the title product as a colourless solid; total yield 95.4%. LC-MS (m/z) 271.5 and 273.3 (major fragment, M-Boc), tR=1.39. 1H NMR (500 MHz, CDCl3) 1.51 (br. s, 9H, tBu), 2.64 (s, 3H, Me), 7.11 (dd, J=8.2 Hz, J=10.6 Hz, 1H, C7H), 3.67 (br. s, 1H, NH), 7.63 (dt, J (d)=4.95 Hz, J (t)=8.1 Hz, 1H, C6H), 7.68 (d, J=8.1 Hz, 1H, C5H). 19F NMR (470.59 MHz, CFCl3=0 ppm), 4:96 mixture of rotamers, −108.9 (br. s, 0.04F), −109.98 (br. s, 0.96F). 13C APT NMR (CDCl3=77.43 ppm): 20.15 (Me), 28.47 (tBu), 83.47 (C of tBu), 113.44 (C), 114.24 (d, J=21.4 Hz, C7H), 122.57 (d, J=4 Hz, C5H), 134.68 (d, J=10.3 Hz, C6H), 138.31 (s, C), 142.69 (s, C), 155.91 (C), 158.42 (C), 161.63 (s, C), 163.74 (s, C).
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[C:6]([O:10][C:11](=[O:27])[NH:12][CH2:13][CH2:14][C@@H:15]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[O:25][CH3:26])[CH2:16][OH:17])([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C@H:15]([CH2:14][CH2:13][NH:12][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:27])[CH2:16][O:17][S:1]([CH3:4])(=[O:3])=[O:2])=[C:19]([O:25][CH3:26])[CH:20]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Br)ccc1[C@@H](CO)CCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(Br)ccc1[C@H](CCNC(=O)OC(C)(C)C)COS(C)(=O)=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
Mesyl chloride (93.7 μL, 1.21 mmol) was added to a solution of [(S)-3-(4-bromo-2-methoxy-phenyl)-4-hydroxy-butyl]-carbamic acid tert-butyl ester (394 mg, 1.0527 mmol) in DCM (7.5 mL) under argon atmosphere at −78° C., followed by addition of TEA (0.336 mL, 2.42 mmol). The mixture was stirred at −78° C. for 1 hour and then at room temperature for an additional hour. A solution of aqueous NaHCO3 (10%) was added, and the organic layer was separated and dried over Na2SO4. Solvent was evaporated under reduced pressure and to afford 480 mg of crude methanesulfonic acid (S)-2-(4-bromo-2-methoxy-phenyl)-4-tert-butoxycarbonylamino-butyl ester. This material was dissolved in THF (4 mL) under Ar atmosphere and cooled to 0° C. KHMDS (0.5 M in toluene, 2.32 mL, 1.158 mmol) was added, and the reaction mixture was stirred for 1 hour at room temperature. A saturated solution of NH4Cl was added, followed by brine, and the resulting mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 98/2) to give 315 mg (84% yield) of (S)-3-(4-bromo-2-methoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 99% ee determined by chiralcel HPLC column and hexane/i-PrOH (9/1) as mobile phase.