Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]=[N+]=[N-])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC1COCC(C2C=CC=C(N)C=2)(CF)N=1)(C)(C)C.[Br:49][C:50]1[CH:51]=[CH:52][C:53]([C:56](O)=[O:57])=[N:54][CH:55]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C([O-])(O)=O.[Na+]>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:56]([C:53]3[CH:52]=[CH:51][C:50]([Br:49])=[CH:55][N:54]=3)=[O:57])[CH:17]=2)([CH2:14][F:15])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(N=[N+]=[N-])c2)COC1
Reactant: O=C(O)c1ccc(Br)cn1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(N)c2)COC1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1=NC(CF)(c2cccc(NC(=O)c3ccc(Br)cn3)c2)COC1
Reaction time: 4 h

Procedure:
A solution of [5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (56 mg, 0.161 mmol) in 2 ml of EtOAc was hydrogenated in the presence of Lindlar catalyst (11 mg) for 3 h. The mixture was filtered through Celite, and the filtrate was evaporated. The crude [5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (50 mg, 0.155 mmol) was taken up in 2 ml of dichloromethane. A mixture of 5-bromo-pyridine-2-carboxylic acid (34.4 mg, 0.170 mmol), HOBT (30.9 mg, 0.17 mmol) and EDC (32.6 mg, 0.17 mmol) in 2 ml of dichloromethane was added, followed by the addition of triethylamine (0.054 ml). The mixture was stirred for 4 h, treated with 5% aqueous NaHCO3 solution and extracted twice with dichloromethane. The organic phase was dried with MgSO4 and evaporated. The residue was chromatographed on silica gel (EtOAc/cyclohexane=1:4) to yield the title compound. TLC (hexane/EtOAc=3:1): Rf=0.16; HPLC: RtH1=2.763 min; 1H-NMR (400 MHz, CDCl3): 9.80 (br, 1H), 8.60 (d, 1H), 8.11 (d, 1H), 7.98 (d, 1H), 7.77 (br, 1H), 7.73 (d, 1H), 7.33 (br, 1H), 7.15 (d, 1H), 4.75-3.65 (m, 6H), 1.60 (br; minor rotamer tBu), 1.42 (br; major rotamer tBu); MS: 507, 509 [(M+H)+].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26]([O:28]CC)=[O:27])[N:24]=2)=[CH:15][CH:14]=1.[OH-].[Na+].Cl>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([CH:31]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26]([OH:28])=[O:27])[N:24]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1csc(C(c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)n1

Procedure:
1.4 g (0.00272 mol) of the compound from Example 2 were dissolved in 20 ml of ethanol, 5 ml of 1N sodium hydroxide solution were added, and the mixture was heated at the boiling point for 2 hours. After cooling, 5 ml of 1N hydrochloric acid were added. The colourless precipitate obtained was filtered off and dried. The product is amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[CH2:32]([OH:37])[CH2:33][CH2:34][C:35]#[CH:36].C(N(CC)CC)C>C1COCC1.CCOC(C)=O.OS([O-])(=O)=O.[K+].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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:36]#[C:35][CH2:34][CH2:33][CH2:32][OH:37])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Reactant: C#CCCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=S(=O)([O-])O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: OCCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
3.0 g (6.846 mmol) Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester were suspended three times with toluene prior to the reaction, then dissolved in 25 ml THF and added to 240 mg (0.34 mmol) PdCl2(PPh3)2. To this suspension 0.67 ml (7.19 mmol) 4-pentyn-1-ol in 1 ml THF were added, followed by 54 mg (0.205 mmol) triphenylphosphine in 1 ml THF and 2.9 ml (20.54 mmol) triethylamine. The solution was stirred for 20 min at RT prior to the addition of 13 mg (0.07 mmol) CuI. The solution was heated to 50° C. overnight. Further 132 μl (1.4 mmol) 4-pentyn-1-ol in 0.8 ml THF were added in two portions and stirring at 50° C. was continued for 5 h and at RT over night. The reaction mixture was diluted with EtOAc and 1M KHSO4. The inorganic phase was extracted with EtOAc and the combined organic phases were washed with water and brine and dried over Na2SO4. Column chromatography with a gradient hexane:EtOAc 2:1 to 1:1 gave 1.83 g (72%) 5-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-pent-4-yn-1-ol as light yellow oil, MS: 371 (M, 1Br).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+]>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:1][C:2]1[N:3]=[N:4][C:5]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cn1cc(-c2ccc(Cl)nn2)cn1
Temperature: 100 °C

Procedure:
In a two-neck flask was placed 3,6-dichloropyridazine (1.49 g, 10 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (1.04 g, 5 mmol), K2CO3 (1.38 g, 10 mmol), and Pd(PPh3)4 (289 mg, 0.25 mmol). The resulting mixture was degassed and refilled with N2 (3 times). 1,4-Dioxane/H2O (9 mL/2 mL) was added and the resulting mixture was heated at 100° C. for 5 h. The resulting mixture was poured into EtOAc/H2O (30 mL/30 mL). The organic layer was washed with brine (30 mL), dried (Na2SO4), and filtered. The solvent was removed and the resulting residue was purified by column using 90-100% EtOAc/hexane as the eluent to yield 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13](NC2C=CC(C3ON=CC=3)=CC=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][C:38]=1[C:39]1[O:43][CH:42]=[N:41][CH:40]=1)[NH2:35]>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:35][C:34]2[CH:36]=[CH:37][C:38]([C:39]3[O:43][CH:42]=[N:41][CH:40]=3)=[C:32]([O:31][CH3:30])[CH:33]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Reactant: COc1cc(N)ccc1-c1cnco1
Product: COc1cc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)ncc2C(N)=O)ccc1-c1cnco1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-methoxy-4-(oxazol-5-yl)aniline in step 1. MS: 424.5 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CCCCCC.C([Li])CCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:37])[C:32](=[C:34]([CH3:36])[CH3:35])[CH:33]=1)([CH3:28])([CH3:27])[CH3:26]>C1COCC1.O>[C:25]([C:29]1[CH:30]=[C:31]([CH3:37])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([CH3:36])[CH3:35])[CH:33]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC1=CC(C(C)(C)C)=CC1=C(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1=CC(C(C)(C)C)=CC1C(C)(C)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 18.2 %

Procedure:
To a solution of 10.1 g (60.8 mmol) of fluorene in 300 ml of THF, 40 ml (61.6 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for 5 hours (dark brown solution). The solution was ice cooled again, and a solution of 11.7 g (66.5 mmol) of 3-tert-butyl-1,6,6-trimethylfulvene in 300 ml of THF was dropwise added in a nitrogen atmosphere. After stirring at room temperature for 14 hours, the resulting brown solution was ice cooled, and 200 ml of water was added. The organic phase extracted with diethyl ether and separated was dried over magnesium sulfate and then filtered. From the filtrate, the solvent was removed under reduced pressure to obtain an orangy brown oil. The oil was purified by silica gel column chromatography (developing solvent: hexane) to obtain 3.8 g of a yellow oil. The analyzed values are given below.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:9]([N:27]=[C:28]=[O:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)=O>[N:4]1([CH2:3][CH2:2][O:1][C:28](=[O:29])[NH:27][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCCN1CCCC1
Temperature: 25 °C

Procedure:
10.1 Grams of N-hydroxyethylpyrrolidine, 23.6 g of octadecyl isocyanate and 100 ml of acetone were charged in a flask equipped with a stirrer and a condenser and refluxed with heating for 3 hours under stirring. The reaction mixture was cooled to room temperature, and the precipitated crystal was filtered off under reduced pressure and washed with acetone, followed by recrystallization from n-hexane to obtained 18.5 g of the desired product. m.p. 57° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34]([OH:36])=O)=[CH:6][N:7]2[CH2:32][CH3:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:71]1([CH2:76][CH2:77][NH2:78])[CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C)C=O>[Cl:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:10]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:37])[C:5]([C:34]([NH:78][CH2:77][CH2:76][N:71]1[CH2:75][CH2:74][CH2:73][CH2:72]1)=[O:36])=[CH:6][N:7]2[CH2:32][CH3:33]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2c(Cl)c(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
To a solution of 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Example 16f) (5 g, 8.68 mmol) in N,N-Dimethylformamide (DMF) (75 mL) was added HATU (3.96 g, 10.42 mmol) and DIPEA (4.55 mL, 26.1 mmol), the resulting mixture was stirred at r.t. for 15 min. Then 2-(pyrrolidin-1-yl)ethanamine (1.502 mL, 9.55 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and partitioned between water and DCM. The organic layer was separated and washed with water (2×), sat. NaHCO3 (aq.) and brine. The organic solution was dried over Na2SO4, and concentrated. The residue was purified by automated silica gel chromatography (CombiFlash Rf) eluting with MeOH/DCM (0-25%), followed by reverse phase chromatography (CombiFlash Rf) eluting with ACN/water (0-100%) to afford 5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (3.6 g, 5.81 mmol, 66.9% yield) as a white solid. LCMS: (M+H)+: 620.5
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]([C:24](=[O:27])[CH2:25][CH3:26])[NH2:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:23][N:22]([CH3:21])[C:24](=[O:27])[CH2:25][CH3:26])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCC(=O)N(C)N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol) in dry DCM (30 mL) were added N-methylpropanehydrazide 225 (0.14 g, 1.35 mmol), 1-hydroxybenzotriazole (0.19 g, 1.35 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.26 g, 1.35 mmol) and 4-(dimethylamino)pyridine (0.16 g, 1.35 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give (2R,5S)-6-(benzyloxy)-N′-methyl-7-oxo-N′-propanoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 226 (0.19 g, 59%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[CH:3]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[Ca+2].[Br:19]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[O:6][C:7]3([C:10](=[O:11])[C:4]=2[C:3]=1[Br:19])[CH2:9][CH2:8]3
Reactant: Nc1ccc2c(c1)C(=O)C1(CC1)O2
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Nc1ccc2c(c1Br)C(=O)C1(CC1)O2
Temperature: -17 °C
Reaction time: 0.75 h

Procedure:
5-Aminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (0.747 g.) and calcium carbonate (0.47 g.) were suspended in a mixture of carbon tetrachloride (20 ml.) and methylene chloride (5 ml.). The suspension was cooled to -17° C., then bromine (0.22 ml.) was added thereto dropwise, followed by stirring for 45 minutes. The reaction mixture was poured into ice-water, then extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated off, and the residue was recrystallized from ethanol-water. By the above procedure there was obtained 5-amino-4-bromospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one as yellow needles melting at 167°-170° C. Yield 0.6 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13](CC)[C@H]2CC[C@H](N(CCOC)C)CC2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N1CCOCC1)C#C.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:13][C:4]1[C:5]([CH3:12])=[C:6]([CH:11]=[C:2]([Br:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#CCN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)cc(N)c1C
Temperature: 105 °C
Yield: 126.5 %

Procedure:
To a solution of methyl 5-bromo-3-(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)amino)-2-methylbenzoate (30 g, 68.02 mmol), 4-(prop-2-yn-1-yl) morpholine (25.51 g, 204 mmol) and triethylamine (20.61 g, 204 mmol) in DMF (300 mL) was bubbled Argon for 20 min. Then CuI (3.87 g, 20.36 mmol) and Pd (PPh3)4 (7.85 g, 6.79 mmol) were added and Argon was bubbled through for further 20 min. The reaction mixture was heated at 105° C. for 4 h and then cooled to room temperature. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with 10% MeOH/DCM (400 mL×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was, purified by silica gel column chromatography to afford the title compound (21 g, 63.7% yield).
Reaction SMILES: [Li].ClC1C=CC=CC=1C.Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][CH:19]=[N:20][N:21]=2)=[CH:13][CH:12]=1.C([Li])CCCCC.C[O:30][B:31](OC)[O:32]C>C1COCC1.C1(C2C=CC=CC=2)C=CC=CC=1.CC(C)CC(=O)C.CO>[O:18]1[CH:19]=[N:20][N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:11]([B:31]([OH:32])[OH:30])=[CH:12][CH:13]=1
Reactant: Brc1ccc(-c2nnco2)cc1
Reactant: COB(OC)OC
Agent: [Li]
Agent: [Li]CCCCCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CC(=O)CC(C)C
Solvent: CO
Product: OB(O)c1ccc(-c2nnco2)cc1
Temperature: -30 °C
Reaction time: 6 h
Yield: 59.7 %

Procedure:
Tetrahydrofuran (250 g) was charged to a mixture of lithium granules (3.02 g) and biphenyl (0.01 g) under an argon atmosphere and the mixture cooled to −30° C. 2-Chlorotoluene (27.55 g) was slowly added at −30° C. The reaction was held at −30° C. for 6 hours and then cooled to −65° C. A mixture of 2-(4-bromophenyl)-1,3,4-oxadiazole (50.0 g) in THF (300 g) was slowly added at −65° C. The reaction was held at −65° C. for 30 minutes then a solution of n-hexyllithium (33% w/w in hexanes, 86 ml) was added at −65° C. The reaction was held at −65° C. for 30 minutes and then trimethylborate (48.7 g) was added at −65° C. The reaction was held at −65° C. for 10 minutes then methanol (55.3 g) was added followed by 4-methyl-2-pentanone (240 g). The reaction mixture was warmed and the low boiling solvents distilled off under vacuum to a maximum temperature of 55° C. The residual mixture was cooled to 0° C. and 10% w/w sulphuric acid (92 g) was added followed by water (92 g) whilst maintaining the temperature below 7° C. Product precipitated. The pH was adjusted to 6.5 by the addition of more 10% w/w sulphuric acid (85.3 g). The mixture was heated to 40° C. then cooled back to 5-10° C. Product was isolated and washed with THF (56 g) and water (60 g), yielding wet title compound (25.2 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[C:15]2=[CH:16][C:17]3[O:21][CH2:20][O:19][C:18]=3[CH:22]=[C:14]2[O:13][CH2:12]1.[CH3:23][N:24](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[O:11]=[C:8]1[C:7]2([C:15]3=[CH:16][C:17]4[O:21][CH2:20][O:19][C:18]=4[CH:22]=[C:14]3[O:13][CH2:12]2)[C:6]2[C:10](=[C:2]([C:23]#[N:24])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: O=C1Nc2c(Br)cccc2C12COc1cc3c(cc12)OCO3
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc2c1NC(=O)C21COc2cc3c(cc21)OCO3
Yield: 76 %

Procedure:
To a suspended mixture of 7′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.44 g, 1.2 mmol) and zinc cyanide (0.28 g, 2.4 mmol) in anhydrous N,N-dimethylformamide (12 mL) was added tetrakis(triphenylphosphine)palladium (0.14 g, 0.12 mmol). The reaction mixture was refluxed for 3 h. The solid was filtered and washed with ethyl acetate (40 mL). The filtrate was concentrated in vacuo to dryness. The residue was purified by column chromatography with ethyl acetate in hexanes (20% to 30% gradient) to afford 2′-oxo-1′,2′-dihydrospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indole]-7′-carbonitrile (0.28 g, 76%) as a colorless solid: mp 205-207° C.; 1H NMR (300 MHz, DMSO-d6) δ11.55 (s, 1H), 7.62 (dd, J=8.0 Hz, 1.1 Hz, 1H), 7.41 (d, J=7.0 Hz, 1H), 7.12-7.07 (m, 1H), 6.69 (s, 1H), 6.44 (s, 1H), 5.93 (dd, J=3.4, 0.8 Hz, 2H), 4.78 (d, J=9.5 Hz, 1H), 4.67 (d, J=9.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ178.4, 155.4, 148.3, 145.2, 141.7, 133.8, 131.6, 128.3, 122.5, 118.9, 115.9, 103.2, 101.3, 93.1, 92.6, 79.6, 57.5; MS (ES+) m/z 307.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32]([O:34]CC)=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:43])[C@@H:13]([NH:19][C:20]([C:22]2[CH:26]=[C:25]([O:27][C:28]3([C:32]([OH:34])=[O:33])[CH2:31][CH2:30][CH2:29]3)[N:24]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:23]=2)=[O:21])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)OCC)CCC3)n(-c3ccccc3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3(C(=O)O)CCC3)n(-c3ccccc3)n2)CC1

Procedure:
To a solution of 70 mg of 4-((S)-4-Carboxy-2-{[5-(1-ethoxycarbonyl-cyclobutoxy)-1-phenyl-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 2 ml of THF, 0.3 ml of a 1 M aqueous NaOH solution was added. After stirring for 1 h at RT additional 0.3 ml of a 1 M aqueous NaOH solution was added and allowed to stir upon completion of the reaction. Then, the reaction was acidified to pH 1 with diluted aqueous hydrochloric acid and extracted with DCM (3×50 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. Yield: 49 mg MS (ES+): m/e=572.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(COC)OC.O.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:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:36])([F:35])[F:24])[CH:31]=2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(C(F)(F)F)c2)cc1
Yield: 56.9 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3-(trifluoromethyl)benzyl)benzamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.060 g; 0.173 mmol), 3-(trifluoromethyl)phenylboronic acid (0.033 g; 0.173 mmol), tetrakis(triphenylphosphine)palladium(0) (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.346 mmol), sodium iodide (0.052 g; 0.346 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) furnished 0.045 g (57%) of the title compound as a white solid.