Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:11]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CS(C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:23]=[CH:24][C:3]([CH2:2][N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[CH:4][CH:5]=2)=[CH:11][C:12]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)cc1
Solvent: CS(C)=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)CC1

Procedure:
4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (1 mL) and stirred for 1 h with methylpiperazine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide. MS (Q1) 421.3 (M)+.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C1(N[C@H]2CC[C@H](C)CC2)CCC1.NC1SC=NC=1.C(OC(=O)CS)C>>[CH:23]1([N:15]([C@H:16]2[CH2:17][CH2:18][C@H:19]([CH3:22])[CH2:20][CH2:21]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:27])=[O:3])=[CH:8][N:9]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: CCOC(=O)CS
Agent: C[C@H]1CC[C@H](NC2CCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC2)CC1

Procedure:
{2-[3-Cyclobutyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester prepared as described in general procedures (A) and (B) using cyclobutyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:12]1[C:13]2[CH:20]=[CH:19][NH:18][C:14]=2[N:15]=[CH:16][N:17]=1.[NH4+].[Cl-]>C1COCC1>[C:3]1([CH2:2][CH2:1][C:12]2[C:13]3[CH:20]=[CH:19][NH:18][C:14]=3[N:15]=[CH:16][N:17]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Br[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: c1ccc(CCc2ncnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.3 %

Procedure:
Phenethyl magnesium bromide (0.5 M solution in THF, 12 mL, 6.15 mmol) was added dropwise to a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.210 g, 1.37 mmol) and Fe(acac)3 (0.1 g 0.273 mmol) in THF (5.0 mL) under Ar. The resulting reaction mixture was stirred at r.t. for 8 h. The mixture was poured onto a mixture of ice (10 mL) and NH4Cl (0.5 g) and the product was extracted with CHCl3. The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 10% MeOH/DCM) to afford the title compound (0.166 g, 54%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:19][C:20]1[CH:25]=[N:24][CH:23]=[C:22](Cl)[N:21]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:16])[N:7]([C:22]1[CH:23]=[N:24][CH:25]=[C:20]([Cl:19])[N:21]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)NCc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of (3-fluoro-benzyl)-carbamic acid tert-butyl ester I-4a (1.21 g, 5.37 mmol) in DMF (50 mL) was treated with 60% NaH in mineral oil (430 mg, 10.7 mmol). The resulting mixture was stirred at ambient temperature until the gas evolution ceased. The solution was treated with 2,6-dichloro-pyrazine (800 mg, 5.37 mmol) and the reaction mixture was heated to 80° C. under N2 and stirred for 5 h. The reaction was cooled and concentrated in vacuo to approximately ⅓ volume. The reaction mixture was poured into H2O (50 mL) and extracted with Ethyl Acetate (1×200 mL). The organic layer was washed with H2O (4×50 mL), brine, dried (Na2SO4), and concentrated to dryness. The crude product was purified by chromatography (EtOAc/Hex 5:95) to afford the title compound I-4b (1.14 g) as a colorless oil.
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](O)=[O:24])[N:21]=1)=[CH:5]2.[CH3:26][NH:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:27]([CH3:28])[CH3:26])=[O:24])[N:21]=1)=[CH:5]2
Reactant: CNC
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Product: CN(C)C(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Yield: 49 %

Procedure:
The compound (50 mg, 0.13 mmol) prepared in Example 27 and dimethylamine instead of morpholine were reacted according to the same procedure as Example 73 to give the title compound (26 mg, Yield 49%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][N:13]2C(OC)=O)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br>>[CH3:1][C:2]1[CH:3]=[C:4]([C@H:12]2[CH2:17][C@H:16]([C:18]3[O:22][NH:21][C:20](=[O:23])[CH:19]=3)[CH2:15][CH2:14][NH:13]2)[CH:5]=[CH:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(C(F)(F)F)c(C)c1
Agent: Br
Product: Cc1cc([C@H]2C[C@H](c3cc(=O)[nH]o3)CCN2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
Trans-methyl 2-(3-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.139 g, 0.36 mmol) was dissolved in HBr (33% in acetic acid, 5.60 g, 22.84 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3-methyl-4-(trifluoromethyl)phenyl)piperidin-4-yl)isoxazol-3(2H)-one (0.075 g, 64%). 1H NMR (600 MHz, dmso) δ 1.76-1.85 (m, 2H), 1.85-1.93 (m, 1H), 1.99-2.07 (m, 1H), 2.40 (d, 2H), 2.67-2.75 (m, 1H), 2.80-2.89 (m, 1H), 3.10-3.17 (m, 1H), 3.68-3.78 (m, 1H), 5.96 (s, 1H), 7.36 (d, 1H), 7.43 (s, 1H), 7.57 (d, 1H). HRMS Calcd for [C16H17F3N2O2+H]+: 327.1320. Found: 327.1298.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11](=O)[CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C.[Pd]>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:20](=[O:22])[CH3:21])=[C:2]([CH3:1])[CH:3]=1)[CH3:18]
Reactant: CCOC(=O)CCC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCc1ccc(NC(C)=O)c(C)c1
Reaction time: 8 h
Yield: 90 %

Procedure:
The product from Example 101 (18.05 g) was dissolved in ethyl acetate (1 L) and subjected to hydrogenation with 20% Pd/C (dry) in the presence of acetic anhydride (15 ml). The reaction mixture was filtered, and the solvent was evaporated. The residue was dissolved in ethanol (250 ml) and a catalytic amount of sulfuric acid (5 drops) was added. The resulting solution was hydrogenated at room temperature overnight. The catalyst was filtered and the filtrate was washed with 5% sodium bicarbonate dried and the solvent was evaporated to afford the desired compound in 90% yield.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].N1CCCCC1.[C:13]([O:18][CH3:19])(=[O:17])/[CH:14]=[CH:15]/[CH3:16]>>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH:15]([CH3:16])[CH2:14][C:13]([O:18][CH3:19])=[O:17]
Reactant: C/C=C/C(=O)OC
Reactant: COC(=O)CS
Solvent: C1CCNCC1
Product: COC(=O)CSC(C)CC(=O)OC
Reaction time: 15 h
Yield: 88.6 %

Procedure:
To a mixture of methyl thioglycolate (45 mL, 503.2 mmol) and piperidine (0.8 mL) at 0° C. was slowly added methyl crotonate (67 mL, 631.7 mmol). Additional piperidine (0.8 mL) was added in two portions after ten and twenty minutes. After stirring for 15 hours, the mixture was purified by vacuum distillation. The fraction was collected at 110-112° C. to give methyl 3-(2-methoxy-2-oxoethylthio)butanoate (92 g, 89%). 1H NMR (CDCl3, 400 MHz) δ 3.75 (s, 3H), 3.70 (s, 3H), 3.38-3.44 (m, 3H), 2.71-2.46 (m, 2H), 1.36 (d, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH3:13])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[O:6].[N:14]([O-])=[O:15].[Na+].Cl.C(Cl)(Cl)Cl.C(OCC)(=O)C.CO>C(O)(=O)C>[Cl:1][CH2:2][CH2:3][N:4]([N:14]=[O:15])[C:5]([N:7]([CH3:13])[CH2:8][CH:9]([OH:12])[CH2:10][OH:11])=[O:6]
Reactant: CN(CC(O)CO)C(=O)NCCCl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(CC(O)CO)C(=O)N(CCCl)N=O
Yield: 62.8 %

Procedure:
2.1 g of 1-(2-chloroethyl)-3-methyl-3-(2,3-dihydroxy-n-propyl)urea are dissolved in 10 ml of acetic acid, and 1.4 g of sodium nitrite are added thereto under stirring. The mixture is stirred at room temperature for 2 hours. Then, 2 ml of concentrated hydrochloric acid and one g of sodium nitrite are added to the mixture, and said mixture is further stirred at the same temperature for 2 hours. After the reaction, the mixture is treated in the same manner as described in Example 60-(2) (Solvent used for chromatography: chloroform-ethyl acetate-methanol(3:1:1)). 1.5 g of 1-(2-chloroethyl)-1-nitroso-3-methyl-3-(2,3-dihydroxy-n-propyl)urea are thereby obtained as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])/[C:6](/[NH:18][C:19](=[O:38])[C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)=[CH:22][C:21]=1[Cl:37])=[CH:7]/[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>CO.O1CCCC1>[Cl:37][C:21]1[CH:22]=[C:23]([C:26](=[O:36])[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([OH:35])[CH:30]=2)[CH:24]=[CH:25][C:20]=1[C:19]([NH:18]/[C:6](=[CH:7]\[C:8]1[CH:9]=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)/[C:5]([OH:39])=[O:4])=[O:38]
Reactant: COC(=O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C(=C/c1cnc2ccccc2c1)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.9 mL, 0.9 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester (Example 226; 140 mg, 0.272 mmol) in methanol/tetrahydrofuran (1:1; 3.6 mL). The solution was stirred at room temperature for 16 h and the solvent was evaporated. Water (7 mL) was added and the mixture was extracted with diethyl ether. The diethyl ether extract was discarded and the water layer was filtered through Celite® and then acidified with 1N hydrochloric acid solution (1 mL). The resulting solid was filtered off, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to give (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (96 mg, 70% yield) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[NH:15][C:14](=[O:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=O)[CH2:9]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.C(OCCO)C.Cl>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[NH:15][C:14](=[O:18])[CH:13]=[C:12]([CH3:19])[C:11]=2[C:10](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:9]1
Reactant: Cc1cc(=O)[nH]c2c1C(=O)CC(c1ccccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCOCCO
Product: Cc1cc(=O)[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Temperature: 135 °C
Reaction time: 1 h
Yield: 157.6 %

Procedure:
To a mixture of 7-(2-chlorophenyl)-4-methyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.144 g) and aminoguanidine hydrochloride (61 mg) were added 2-ethoxyethanol (2.5 ml) and concentrated hydrochloric acid (0.1 ml), and the mixture was stirred at 135° C. for 1 hour and cooled. Precipitated crystals were filtered, washed with methanol and dried to give 7-(2-chlorophenyl)-5-guanidinoimino-4-methyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 139) (0.15 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:16]2[N:15]=[C:14]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7].[OH:25][C:26]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>CS(C)=O.C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:16]2[N:15]=[C:14]([NH:17][CH2:18][CH:19]3[CH2:20][CH2:21][N:22]([CH2:28][C:27]4[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:26]=4[OH:25])[CH2:23][CH2:24]3)[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COCCNC(=O)c1cccc2[nH]c(NCC3CCNCC3)nc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: COCCNC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)ccc4O)CC3)nc12
Temperature: 50 °C
Reaction time: 48 h

Procedure:
After dissolving 2-[(piperidin-4-ylmethyl)-amino]-1H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl)-amide (20 mg, 0.049 mmol) in dimethylsulfoxide-acetic acid (10:1, 0.50 ml), 2-hydroxy-5-chlorobenzaldehyde (23 mg, 0.15 mmol) and sodium triacetoxyborohydride (31 mg, 0.15 mg) were added and the mixture was stirred at 50° C. for 2 days. Methanol (1 ml) was added to the reaction mixture, and after stirring for 1 minute, the mixture was purified by SCX solid phase extraction (Bond Elute SCX500MG). The product was further purified by preparative HPLC to obtain 2-{[1-(5-chloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid (2-methoxy-ethyl)-amide. The compound was identified by LC-MS.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:12]#[C:11][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccnc1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 4.0 g (15 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 2.0 g (19 mmol) 3-ethynyl-pyridine using 282 mg (1.5 mmol) CuI, 1.0 g (1.5 mmol) PdCl2(PPh3)2 and 21 mL (148 mmol) triethylamine in 200 mL dry DMF. For the work-up the reaction mixture is concentrated in vacuo before water is added. The precipitate is collected, dried at 40° C. and crystallized from MeOH/H2O. Yield: 3.0 g (83%).
Reaction SMILES: [CH2:1]([C@@H:5]([C:22](=[O:29])[NH:23][CH2:24][C:25]([O:27]C)=[O:26])[NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]([CH3:4])[CH3:3].O[Li].O>C1COCC1.O>[CH2:1]([C@@H:5]([C:22](=[O:29])[NH:23][CH2:24][C:25]([OH:27])=[O:26])[NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@H](NC(=O)CCCCCNC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oate (6w) in THF was added a solution of LiOH.H2O in water at room temperature. After 3 h, the reaction mixture was concentrated, diluted with water and acidified with a 1N aqueous solution of HCl to about pH 4-5. The mixture was stirred for 15 min and the white precipitate formed was filtered off, rinsed with water, and dried to afford (S)-13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oic acid (7w).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3ccc(F)cc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2cnn(C3CCNCC3)c2c1
Reaction time: 1 h

Procedure:
To tert-butyl 4-(6-fluoro-1H-indazol-1-yl)piperidine-1-carboxylate prepared as in STEP 1 above (998 mg, 3.10 mmol) in DCM (20 mL) at 0° C. was added TFA (10 mL). The resulting mixture was then stirred for 1 hour. The solvent was removed in vacuo. To the resulting residue was added 0.5N NaOH (15 mL), followed repeated extraction with CHCl3. The organic layer was dried with MgSO4 and filtered to yield 6-fluoro-1-(piperidin-4-yl)-1H-indazole.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:29][CH3:30])=[CH:19][C:20]([CH2:27][CH3:28])=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.C(=O)(O)[O-].[Na+].Br[C:38]#[N:39]>O1CCOCC1>[NH2:39][C:38]1[O:23][C:22]([C:21]2[C:20]([CH2:27][CH3:28])=[CH:19][C:18]([CH2:29][CH3:30])=[C:17]([CH:26]=2)[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[O:16])=[N:24][N:25]=1
Reactant: CCc1cc(CC)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)NN
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(CC)c(-c2nnc(N)o2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 0.08 h
Yield: 105.8 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide (compound 204.7, 100 mg, 0.220 mmol, 1.00 equiv, 90%) in a solvent mixture of water (2 mL) and dioxane (3 mL). Sodium bicarbonate (62 mg, 0.740 mmol, 3.00 equiv) was added to the reaction mixture at room temperature, and stirred for 5 minutes. BrCN (75 mg, 0.740 mmol, 3.00 equiv) was then added to the reaction at room temperature. The resulting solution was stirred for 2 h at room temperature, then quenched with 30 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 100 mg (89%) of the title compound as a yellow solid. The compound was used in the next step reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH2:20])[C:6]1[CH:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[CH:8][CH:7]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27][C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C@@H:5]([NH:20][C:28](=[O:29])[CH2:27][O:26][CH2:25][CH2:24][O:23][CH3:22])[C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1
Reactant: COCCOCC(=O)O
Reactant: COC(=O)C[C@@H](N)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCC(=O)N[C@H](CC(=O)OC)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (R)-3-amino-3-[4-(tert-butoxycarbonylamino)phenyl]-propanoic acid methyl ester [0.75 g, Reference Example 7(c)], 2-(2-methoxyethoxy)acetic acid (0.3 ml), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.02 g), diisopropylethylamine (0.9 ml) and dimethylformamide (25 ml) was stirred at ambient temperature 2 hours. The reaction mixture was poured into water (150 ml) and the resultant solid collected. The resulting fawn solid (1.5 g) was dissolved in dichloromethane (15 ml) and the solution was treated with trifluoracetic acid (3 ml). After stirring at ambient temperature for 2 hours the reaction mixture was evaporated. The residue was treated with toluene (50 ml), concentrated to dryness and the resultant material treated with ethyl acetate (50 ml). The resultant suspension was treated with saturated aqueous potassium carbonate solution (20 ml) with stirring at ambient temperature for 5 minutes. The organic layer was separated, dried over magnesium sulphate, and then evaporated to give the title compound (0.5 g) as a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](F)(=[O:35])=[O:34].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][O:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:33]([C:28]3[C:27]([CH3:26])=[CH:32][CH:31]=[CH:30][CH:29]=3)(=[O:35])=[O:34])=[CH:16][CH:15]=2)[CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Cc1ccccc1S(=O)(=O)F
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccccc1S(=O)(=O)c1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 4-benzyl-6-(4-bromo-phenyl)-morpholine (0.55 g; 1.66 mmol) in THF (25 mL) was added drop wise a solution of n-BuLi in hexanes (1.32 ml; 2.50 mol/1; 3.31 mmol), at −78° C. The resulting mixture was stirred at −78° C., for 30 min. and then 2-methyl-benzenesulfonyl fluoride (0.63 g; 3.64 mmol) was added. After complete addition the mixture was allowed to come to room temperature, and treated with EtOAc and a 5% aqueous NaHCO3-solution. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O) to afford 4-benzyl-2-[4-(toluene-2-sulfonyl)-phenyl]-morpholine (0.50 g). The required 2-methyl-benzenesulfonyl fluoride was prepared as follows: To a solution of o-toluenesulfonyl chloride (0.70 mL; 4.85 mmol) in CH3CN (15 mL) was added spray-dried KF (1.13 g; 19.4 mmol). The resulting mixture was stirred at RT for 18 hours, treated with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 2-methyl-benzenesulfonyl fluoride (0.68 g).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[C:9]([O:13][C:14](=[O:29])[NH:15][C:16]1[C:20]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][S:18][CH:17]=1)([CH3:12])([CH3:11])[CH3:10]>C(Cl)(Cl)(Cl)Cl>[C:9]([O:13][C:14](=[O:29])[NH:15][C:16]1[C:20]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:19][S:18][C:17]=1[Br:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)Nc1cscc1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)Nc1csc(Br)c1NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
NBS (1.22 g, 6.87 mmol) was added to a solution of compound 57 (2.16 g, 6.87 mmol) in CCl4 (137 mL) at r.t. The mixture was stirred for 16 h. The solid material was filtered off and the filtrate was collected and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuum. The residue was purified by flash chromatography with DCM as an eluent affording the title compound 58 (1.92 g, 71% yield). 1H NMR: (CDCl3) δ(ppm): 7.30 (bs, 1H), 6.00 (s, 1H), 1.45 (s, 9H), 1.43 (s, 9H). m/z: 415.4/417.4 (M+Na/M+2+Na). This procedure is essentially as described in Brugier et al., Tetrahedron, 56: 2985-2993 (2000), which is incorporated by reference in its entirety.