Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[F:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)[CH2:7][CH2:8][CH2:9][CH3:10].[CH:31](=[O:34])[CH2:32][CH3:33].Cl>CCCCCC.O1CCCC1>[CH2:6]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:31]([OH:34])[CH2:32][CH3:33])=[C:25]([F:29])[C:24]=3[F:30])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCC=O
Reactant: CCCCCc1ccc(-c2ccc(-c3cccc(F)c3F)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc(-c3ccc(C(O)CC)c(F)c3F)cc2)cc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
6.45 ml of 1.6N butyllithium solution in n-hexane are added dropwise within 5 minutes at -50° C. to a solution of 3.15 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluorobenzene and the reaction mixture is left to react at the same temperature for 3 hours. Then, a solution of 652 mg of propionaldehyde in 4 ml of tetrahydrofuran is added and the mixture is left to warm slowly to room temperature. After 15 hours it is treated with 10 ml of 1N hydrochloric acid, partitioned between methylene chloride and water, the organic phase is washed with saturated sodium bicarbonate solution and dried over anhydrous magnesium sulphate. Evaporation of the solvent and chromatography of the residue on silica gel with 5-20% ethyl acetate in petroleum ether gives 3.2 g of 1-[4-(4-pentylphenyl)-phenyl]-2,3-difluoro-4(1-hydroxypropyl)-benzene.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[NH2:17][C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([O:31][CH3:32])[CH:25]=2)=[CH:20][C:19]=1[C:33]1[O:34][C:35]2[C:36]([N:41]=1)=[N:37][CH:38]=[CH:39][CH:40]=2.[O:42]1[CH2:47][CH2:46][N:45]([CH2:48][CH2:49]O)[CH2:44][CH2:43]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:32][O:31][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[C:19]([C:33]3[O:34][C:35]4[C:36]([N:41]=3)=[N:37][CH:38]=[CH:39][CH:40]=4)[C:18]([NH2:17])=[N:23][CH:22]=2)[CH:29]=[CH:28][C:27]=1[O:30][CH2:49][CH2:48][N:45]1[CH2:46][CH2:47][O:42][CH2:43][CH2:44]1
Reactant: OCCN1CCOCC1
Reactant: COc1cc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)ccc1O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(-c2cnc(N)c(-c3nc4ncccc4o3)c2)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
[C2] A solution of di-tert-butyl azodicarboxylate (241 mg) in dichloromethane (1 ml), was added dropwise to a stirred suspension of 4-(6-amino-5-(oxazolo[4,5-b]pyridin-2-yl)pyridin-3-yl)-2-methoxyphenol (130 mg), 2-morpholinoethanol (0.054 ml) and triphenylphosphine polymer bound (350 mg, 1.05 mmol) dissolved in dichloromethane (3 ml). The resulting suspension was stirred at room temperature for 2 hours. The mixture was filtered, washed with dichloromethane (1 ml) and methanol (1 ml). The solvent was evaporated. The resulting residue was diluted with 1 ml of dichloromethane and 1 ml of TFA; the mixture was stirred overnight and concentrated. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 5-[3-methoxy-4-(2-morpholinoethoxy)phenyl]-3-oxazolo[4,5-b]pyridin-2-yl-pyridin-2-amine (70 mg) as a solid. The 4-(6-amino-5-oxazolo[4,5-b]pyridin-2-yl-3-pyridyl)-2-methoxy-phenol used as starting material was made as follows:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C:4](=[O:8])[CH2:3]1.I[C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[C:4](=[O:8])[CH2:3]1
Reactant: CN1CCNC(=O)C1
Reactant: Nc1ccc(I)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(N)cc2)C(=O)C1
Temperature: 110 °C
Yield: 7 %

Procedure:
A mixture of 4-methyl-2-piperazinone (200 mg, 1.75 mmol), 4-iodoaniline (384 mg, 1.75 mmol), K3PO4 (848 mg, 4.00 mmol) and 1,2-trans-diaminocyclohexane (98 uL, 0.80 mmol) in dioxane (6 mL) was degassed with Ar before being charged with CuI (76 mg, 0.40 mmol). The mixture in a sealed tube was heated at 110° C. for 4 h. It was then purified by a silica gel prep-TLC using CH2Cl2/MeOH (95/5) as solvents to give the desired product (25 mg). MS 206.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH:28]CC6C=CC(OC)=CC=6)=[N:25][N:24]=5)[CH:21]=4)[N:16](S(C4C=CC(C)=CC=4)(=O)=O)[CH:15]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.FC1C=CC(C2N=C(C3C4C(=CC=C(C5OC(N)=NN=5)C=4)N(S(C4C=CC(C)=CC=4)(=O)=O)C=3)C=NC=2)=CC=1.[OH-].[Na+]>C(O)(C(F)(F)F)=O.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]5[O:27][C:26]([NH2:28])=[N:25][N:24]=5)[CH:21]=4)[NH:16][CH:15]=3)[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(-c5ccc(F)cc5)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(-c4ccc(F)cc4)n3)c3cc(-c4nnc(N)o4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: Nc1nnc(-c2ccc3[nH]cc(-c4cncc(-c5ccc(F)cc5)n4)c3c2)o1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A solution of 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (200 mg, 0.309 mmol) in TFA (1 ml) was heated to 100° C. in microwave for 30 min. The mixture was cooled to RT and TFA was removed in vacuo to give the crude material (130 mg, 80%). MS (ESI, pos. ion) m/z: 527 (M+1). To a solution of crude 5-(3-(6-(4-fluorophenyl)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (130 mg, 0.247 mmol) in p-dioxane (1.3 mL) was added aq 10% NaOH (0.65 mL). The mixture was heated at 100° C. for 2 h and quenched with ice cold H2O. The resulting precipitate was filtered and washed with H2O. The crude was recrystallized with 10% MeOH/CHCl3 to give 5-(3-(6-(4-fluorophenyl)-pyrazin-2-yl)-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (25 mg, 27.3%) as an off-yellow solid. MS (ESI, pos. ion) m/z: 374.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 9.17 (s, 1H), 9.06 (s, 1H), 9.00 (s, 1H), 8.53 (m, 1H), 8.37-8.34 (m, 2H), 8.75-8.73 (m, 1H), 7.64 (d, J=8 Hz, 1H), 7.49 (m, 2H), 7.12 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7])([O-])=O.[N+](C1C([N+]([O-])=O)=C(C=CC=1)C=O)([O-])=O>C(O)(=O)C.C(OCC)(=O)C.O.[Fe]>[NH2:1][C:4]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Fe]
Agent: O=Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccc(C=O)c(N)c1
Temperature: 35 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To a nitrogen purged 5 liter 4-neck flask fitted with a condenser, mechanical stirrer, addition funnel, and temperature probe, was added 325 mesh iron dust, which can be obtained from Aldrich, Milwaukee, Wis. (220 g, 3.9 mol, 8 equiv), water (800 mL), and glacial acetic acid (5 mL). Over the next hour, some frothing occurred and the temperature rose to 28° C. In a separate container, 2,4-dinitrobenzaldehyde (97 g, 0.49 mol, 1 equiv) was dissolved in 1:1 glacial acetic acid/ethyl acetate (800 mL). 2,4-Dinitrobenzaldehyde can be purchased from Aldrich, Milwaukee, Wis. About 5 mL of the 2,4-dinitrobenzaldehyde solution was added dropwise to the iron mixture, which led to a dissipation of the frothing. The reaction mixture was warmed to 35° C. with a steam bath. Without further heating, the remaining dinitrobenzaldehyde solution was added at such a rate as to maintain the temperature below 50° C. The addition was completed after 6 hours. The reaction mixture was diluted with water (1 L) and diatomaceous earth (BNL Fine Chemicals and Reagents, Meriden, Conn.) was added (100 g). The reaction mixture was stirred an additional 3 hours at which point the temperature had dropped to 25° C. The solids were removed by filtration. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×400 mL). The extracts were then used to wash the solids from the initial filtration. The organic layers were combined and washed with water (400 mL) and saturated aqueous NaHCO3 (3×400 mL). The combined organic layers were dried over MgSO4 and Darco G-60® (activated charcoal; BNL Fine Chemicals and Reagents, Meriden, Conn.) (10 g). After filtration to remove the drying agents, the organic layers were concentrated in vacuo to a slurry and diluted with 1 L of hexanes. The precipitated solids were collected by suction filtration and dried in air to give 2,4-diaminobenzaldehyde (48 g, 71%) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)=O.C(O)C.[NH2:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(OC(C)C)(C)C>C(OCC)(=O)C>[N:21]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=2)=[CH:2][N:23]2[CH:24]=[CH:25][CH:26]=[N:27][C:22]=12
Reactant: CCOC(=O)C(C)c1ccc(C(=O)CCl)cc1
Reactant: Nc1ncccn1
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: CCOC(=O)C(C)c1ccc(-c2cn3cccnc3n2)cc1
Yield: 28.4 %

Procedure:
A mixture of 25.5 g of ethyl 2-[4-(chloroacetyl)phenyl]propionate, 50 ml of ethanol and 19 g of 2-aminopyrimidine is heated under reflux for 3 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is extracted with ethyl acetate, and the extract is washed with water, dried and concentrated to give a reddish brown oil. To the oil are added ethyl acetate and isopropyl ether, and the crystalline precipitate is filtered off and recrystallized from ethanol to give 8.4 g of ethyl 2-[4-(imidazo[1,2-a]pyrimidin-2-yl)phenyl]propionate as colorless scales melting at 171°-173°C.
Reaction SMILES: C(O[C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1)C.[CH2:32]([CH2:34][NH2:35])[OH:33].C([O-])([O-])=O.[K+].[K+]>CCO>[OH:33][CH2:32][CH2:34][NH:35][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH:30]=[CH:29][CH:28]=[N:27]5)[CH:21]=4)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH:6]=1
Reactant: NCCO
Reactant: CCOC(=O)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NCCO)c1cccc(-c2ccn3c(-c4cccc(-n5cccn5)c4)cnc3c2)c1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
3-[3-(3-Pyrazol-1-yl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-benzoic acid ethyl ester (Ex. 1.10) (1 eq, 0.098 mmol, 40 mg) and ethanol amine (10 eq, 0.98 mmol, 0.06 ml) are dissolved in EtOH (2 ml) and K2CO3 (1.5 eq, 0.147 mmol, 20.3 mg) is added. The reaction mixture is stirred for 5 h at 55° C. The solvent is removed in vacuo and the reaction is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield N-(2-hydroxy-ethyl)-3-[3-(3-pyrazol-1-yl-phenyl)-imidazo-[1,2-a]-pyridin-7-yl]-benzamide as a white solid; [M+H]+=424
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:6]=1.[C:11]1([CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH:8]1([CH2:7][N:5]2[N:4]=[N:3][C:2]([NH:1][C:18](=[O:19])[CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:6]2)[CH2:10][CH2:9]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Nc1nnn(CC2CC2)n1
Product: O=C(Nc1nnn(CC2CC2)n1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 147-148° and MS: m/e=334.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-cyclopropylmethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][F:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][CH2:40][O:41][CH3:42])[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]=1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:27][C:28]1[CH:36]=[C:35]([C:37]#[C:38][CH2:39][CH2:40][O:41][CH3:42])[C:31]2[O:32][CH2:33][O:34][C:30]=2[C:29]=1[NH:43][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][F:26])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COCCC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(CCF)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCN(CCF)CC4)c(OC)cc23)c2c1OCO2
Yield: 59.9 %

Procedure:
This was prepared by the method described in example 4 using 4-chloro-7-{3-[4-(2-fluoroethyl)piperazin-1-yl]propoxy}-6-methoxyquinazoline (200 mg, 0.52 mmol), 5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-amine (146 mg, 0.57 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.10 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (187 mg, 60%) as colourless solid, NMR Spectrum:(CDCl3) 2.10 (quintet, 2H), 2.57 (m, 8H), 2.67 & 2.72 (dt, 2H), 2.74 (t, 2H), 3.41 (s, 3H), 3.60 (t, 2H), 3.98 (s, 3H), 4.23 (t, 2H), 4.51 & 4.63 (dt, 2H), 6.06 (s, 2H), 6.85 (s, 1H), 7.04 (s, 1H), 7.08 (s, 1H), 7.28 (s, 1H), 8.61 (s, 1H); Mass Spectrum: M+H+ 600/602
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:41]1[CH:46]=[C:45]([C:47]([OH:49])=O)[N:44]=[CH:43][C:42]=1[C:50]([OH:52])=O.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Br:32][C:28]1[CH:27]=[C:26]2[C:31](=[CH:30][CH:29]=1)[C:22]([CH2:21][N:18]1[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=3[N:15]([C:47]([C:45]3[CH:46]=[N:41][C:42]([C:50]([N:15]4[C:16]5[CH:38]=[CH:37][CH:36]=[CH:35][C:17]=5[N:18]([CH2:21][C:22]5[C:31]6[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=6)[CH:25]=[CH:24][C:23]=5[O:33][CH3:34])[C:19](=[O:20])[C@@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:40])[CH3:8])[CH3:10])[CH2:14]4)=[O:52])=[CH:43][N:44]=3)=[O:49])[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([CH3:8])[C:6](=[O:40])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])[C:19]1=[O:20])=[C:23]([O:33][CH3:34])[CH:24]=[CH:25]2
Reactant: O=C(O)c1cnc(C(=O)O)cn1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CN(C(=O)c2cnc(C(=O)N3C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc4c(OC)ccc5cc(Br)ccc45)c4ccccc43)cn2)c2ccccc21
Reaction time: 5 h
Yield: 16 %

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (300 mg, 0.49 mmol) and pyrazine-2,5-dicarboxylic acid (41.2 mg, 0.24 mmol) in pyridine (5 mL) at 0° C. was added POCl3 (46 μL, 0.49 mmol) and the cooling bath removed. After 5 h, the mixture was diluted with dichloromethane, washed with water, dried (Na2SO4) and concentrated. The residue was purified by preparative reverse phase HPLC to afford tert-butyl N-[(1S)-2-[[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-1-[5-[(3S)-5-[(6-bromo-2-methoxy-1-naphthyl)methyl]-3-[[(2S)-2-[tert-butoxycarbonyl(methyl)amino]propanoyl]amino]-4-oxo-2,3-dihydro-1,5-benzodiazepine-1-carbonyl]pyrazine-2-carbonyl]-4-oxo-2,3-dihydro-1,5-benzodiazepin-3-yl]amino]-1-methyl-2-oxo-ethyl]-N-methyl-carbamate (52 mg, 7.82%) as an off white solid. LC-MS: 1355.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]2[C:22]3([CH2:27][CH:26]=[CH:25][CH2:24]3)[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([CH:9]3[CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:28][CH3:29])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:23]2[C:22]3([CH2:27][CH2:26][CH2:25][CH2:24]3)[N:10]3[CH2:11][CH2:12][C:13]4[C:18]([CH:9]3[CH2:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:28][CH3:29])=[CH:17][C:16]1[O:19][CH2:20][O:21][C:15]=1[CH:14]=4
Reactant: COc1ccc2c(c1OC)C1(CC=CC1)N1CCc3cc4c(cc3C1C2)OCO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1OC)C1(CCCC1)N1CCc3cc4c(cc3C1C2)OCO4
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 9′,10′-dimethoxy-5′,6′,13′,13a′-tetrahydrospiro[cyclopent-3-ene-1,8′-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline] (300 mg, 0.75 mmol) in methanol (20 mL) was added sodium borohydride (57 mg, 1.5 mmol) in small portions at 25° C. After stirring at 25° C. for 2 h, the reaction solvent was concentrated in vacuo. The resulting residue was extracted with diethyl ether (2×50 mL), washed with water (2×25 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 9′,10′-dimethoxy-5′,6′,13′,13a′-tetrahydrospiro [cyclopentane-1,8′-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline] (155 mg, 52%). LC/MS m/e calcd for C24H27NO4 (M+H)+: 394.49, observed: 394.3; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.80 (m, 2 H) 1.85-1.96 (m, 2 H) 1.96-2.08 (m, 2 H) 2.16-2.25 (m, 1 H) 2.25-2.35 (m, 1 H) 2.56-2.65 (m, 2 H) 2.65-2.71 (m, 2 H) 2.93-3.03 (m, 2 H) 3.78 (d, J=6.57 Hz, 6 H) 3.91 (d, J=7.83 Hz, 1 H) 5.94 (d, J=3.54 Hz, 2 H) 6.65 (s, 1 H) 6.73 (d, J=8.34 Hz, 1 H) 6.84 (s, 1 H) 6.88 (d, J=8.34 Hz, 1 H).
Reaction SMILES: [CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[CH:27][C:22]3[N:23]([CH3:26])[N:24]=[N:25][C:21]=3[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:29])[C:5]1[C:6]([C:19]2[CH:28]=[CH:27][C:22]3[N:23]([CH3:26])[N:24]=[N:25][C:21]=3[CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc4c(c3)nnn4C)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2c(c1)nnn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
To a solution of methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)quinoxaline-6-carboxylate (110 mg, 0.28 mmol) in methanol (10 ml) was added sodium hydroxide (45 mg, 1.12 mmol) and water (2 ml). The resulting solution was stirred for 2 h at room temperature and concentrated under vacuum, diluted with water (10 ml), and the pH adjusted to 4 with HCl (3N). The solid was collected by filtration to afford 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)quinoxaline-6-carboxylic acid as a yellow solid (56.2 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([OH:18])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:44]([N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(OCC)C.C(OCC)(=O)C.CN(C=O)C>[CH2:44]([N:51]1[CH2:56][CH2:55][N:54]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:18])[CH2:53][CH2:52]1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(F)cc1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C(c1cc2ccccc2n1Cc1ccc(F)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 71.7 %

Procedure:
The following was added sequentially to anhydrous DMF: 1-(4-fluorobenzyl)-1H-indole-2-carboxylic acid (50 mg, 0.186 mmol), Hunig's Base (0.065 ml, 0.371 mmol), EDC (46.3 mg, 0.241 mmol), HOBT (37.0 mg, 0.241 mmol), and 1-benzylpiperazine (32.7 mg, 0.186 mmol). The solution was allowed to stir at room temperature for 22 h. At this time, a 1:1 solution of diethylether/ethyl acetate (5 mL) was added, and this was washed with aqueous 10% Na2CO3 (3×2 mL). The extract was then dried with anhydrous MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by column chromatography (20 g silica, 80% EtOAC/Hexanes) to provide 57 mg of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]([NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])(C(C)(C)C)(C)C.[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]3([CH2:34][O:33][CH2:32]3)[O:30][C:29](OC)=[N:28][S:27]2(=[O:38])=[O:37])=[CH:22][CH:21]=1>ClCCl>[C:20]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:25]=[CH:24][C:23]([CH:26]2[C:31]3([CH2:32][O:33][CH2:34]3)[O:30][C:29]([NH:19][C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[CH2:10][CH2:9][OH:8])=[N:28][S:27]2(=[O:37])=[O:38])=[CH:22][CH:21]=1
Reactant: COC1=NS(=O)(=O)C(c2ccc(-c3ccccc3)cc2)C2(COC2)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1F
Solvent: ClCCl
Product: O=S1(=O)N=C(N[C@@H](CCO)c2ccccc2F)OC2(COC2)C1c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a round-bottom flask, 9-biphenyl-4-yl-6-methoxy-2,5-dioxa-8-thia-7-azaspiro[3.5]non-6-ene 8,8-dioxide was dissolved under inert gas in 2 ml of dichloromethane, and 151 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-(2-fluorophenyl)propylamine were added. After concentration by rotary evaporation, the residue was left to stand at room temperature for 18 hours. To detach the protecting group, the residue was taken up in 1 ml of methanol and, after addition of 0.05 ml of concentrated hydrochloric acid, stirred at room temperature for 1 hour. After concentration by rotary evaporation, the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined and freed of the solvent under reduced pressure. This gave the product (8 mg) with a molecular weight of 496.6 g/mol (C26H25FN2O5S); MS (ESI): m/e=497 (M+H+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.[I:25]N1C(=O)CCC1=O.[CH2:33]([Sn:37]([CH2:46]O)([CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>O.C(OCC)C>[CH2:33]([Sn:37]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:46][I:25])[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](CO)(CCCC)CCCC
Reactant: O=C1CCC(=O)N1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCCC[Sn](CI)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a mixture of triphenylphosphine (70 g, 0.27 mol) and tetrahydrofuran (500 mL) was added dropwise a mixture of N-iodosuccinimide (60 g, 0.27 mol) and tetrahydrofuran (500 mL) at 0° C., and then the reaction mixture was stirred for 30 minutes at 0° C. To this mixture was added dropwise tributylstannyl-methanol (71 g, 0.22 mol) described in Manufacturing Example 197-2-1 at 0° C., and then the reaction mixture was stirred for 20 minutes at 0° C. The reaction mixture was stirred overnight at room temperature. Diethyl ether and water were added to the reaction mixture, and the organic layer was separated. The organic layer was washed first with a saturated sodium thiosulfate aqueous solution and then with saturated aqueous sodium chloride. The organic layer was separated, and was concentrated under a reduced pressure. Heptane (400 mL) was added to the residue and filtered. The solvent in the filtrate was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane) to obtain the title compound (90 g, 94%).