Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](Cl)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.OC=[C:16]1[C:24]2[C:19](=[CH:20][C:21]([C:25]([C:27]3[CH:28]=[C:29]([NH:33]C(=O)C)[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:37]>C1COCC1>[O:37]=[C:17]1[CH2:16][C:24]2[C:19](=[CH:20][C:21]([C:25]([C:27]3[CH:28]=[C:29]([NH:33][C:7]([C:5]4[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=4)=[O:8])[CH:30]=[CH:31][CH:32]=3)=[O:26])=[CH:22][CH:23]=2)[NH:18]1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)c(C(F)(F)F)n1
Temperature: 25 °C
Yield: 79 %

Procedure:
A dry 25 mL flask was charged with 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.186 g, 0.873 mmol) and THF (2 mL). 6-(4-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature. The room temperature reaction mixture was concentrated in vacuo. The light yellow solids were washed with THF (˜3 mL) and filtered to afford the pure product 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.235 g, 0.627 mmol, 79%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH:6]([O:8][CH3:9])[O:5][CH:4]1[O:10][CH3:11].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:11][O:10][CH:4]1[CH:3]([CH2:2][NH:1][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:7][CH:6]([O:8][CH3:9])[O:5]1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC1CC(CN)C(OC)O1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1CC(CNC(=O)c2ccccc2)C(OC)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.4 %

Procedure:
10 g (62 mmol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran and 17 ml (123 mmol) of triethylamine were dissolved in 100 ml of anhydrous tetrahydrofuran. At 0° C., 7.2 ml (62 mmol) of benzoyl chloride were added dropwise and the mixture was stirred at 0° C. for 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. 17 g of crude product were obtained and were immediately reacted further.
Reaction SMILES: C(OC1C=CC(OCC[N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=CC=1)C1C=CC=CC=1.[ClH:30]>CCO>[C:22]1([N:19]2[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[ClH:30]
Reactant: c1ccc(COc2ccc(OCCN3CCN(c4ccccc4)CC3)cc2)cc1
Agent: Cl
Solvent: CCO
Product: c1ccc(N2CCNCC2)cc1

Procedure:
35.75 g of 1-[2-(-4-benzyloxyphenoxy)ethyl]-4-phenylpiperazine PG,58 was added rapidly with stirring to 75 ml concentrated HCl and the mixture was heated on a steam bath for 15 minutes. During this time starting material dissolved and then a white crystalline solid began to form and eventually the reaction mixture almost solidified. The reaction was cooled to ~5° and then was diluted with 100 ml EtOH. The solids were filtered off and were washed in EtOH and ether to give 1-]2-(4-hydroxyphenoxy)ethyl]-4-phenylpiperazine as its monohydrochloride. The salt was dissolved in 150 ml hot MeOH and 50 ml H2O and was then treated with 25 ml triethylamine. Water was then added to the refluxing mixture just to the cloud print whereupon the product began to crystallize from solution. The mixture was chilled and the solids were collected by filtration to give the end product, mp 142°-143°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[BH4-].[Na+]>C(O)C.O>[N+:1]([C:4]1[CH:5]=[C:6]([C:9]([S:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)c(CO)c1
Reaction time: 6 h

Procedure:
450 g of 3-nitro-6-(phenylthio)-benzaldehyde are suspended in 4 litres of ethanol and treated portionwise with 111 g of sodium borohydride. The mixture is stirred for a further 6 hours. The mixture is then diluted with 4 litres of water and extracted with ether. The organic solution is washed successively with water and aqueous sodium bicarbonate solution, dried over magnesium sulphate and evaporated under reduced pressure. The crude product is recrystallised from benzene/petroleum ether. There is obtained 3-nitro-6-(phenylthio)-benzyl alcohol of melting point 104°-107° C.
Reaction SMILES: [CH2:1]1[C:6]2([C:15](=[S:16])[NH:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([N:23]=[C:24]=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C-]#N.[K+].N12CCN(CC1)CC2>C1C=CC=CC=1>[CH2:17]([NH:23][C:24]([N:14]1[C:15](=[S:16])[C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:7][C:8]21[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: S=C1NC2(CCCCC2)NC12CCCCC2
Reactant: CCCCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: c1ccccc1
Product: CCCCCCNC(=O)N1C(=S)C2(CCCCC2)NC12CCCCC2

Procedure:
4.8 Parts of 7,14-diazadispiro[5.1.5.2]pentadecane-15-thione, 2.6 parts of n-hexyl isocyanate, 0.2 parts of potassium cyanide and a trace of 1,4-diazabicyclo[2.2.2]octane in 100 parts of dry benzene were heated at reflux for 48 hours. The solution was treated as in Example 22 to yield 8.0 parts of a yellow oil which was purified by column chromatography (silica gel) to yield 5.33 parts of 14-n-hexylcarbamoyl-7,14-diazadispiro[5.1.5.2]pentadecane-15-thione as a heavy oil. This material gave the following elemental analysis by weight:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[CH:20]=[C:19]([N:23]=[N+:24]=[N-:25])[N:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(Cl)ncn2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(Cc2cc(N=[N+]=[N-])ncn2)cc1
Temperature: 80 °C

Procedure:
A suspension of [4-(6-chloro-pyrimidin-4-ylmethyl)-phenyl]-carbamic acid tert-butyl ester (see Example 117) (1.1 g, 3.44 mmol) and sodium azide (0.31 g, 4.81 mmol, 1.4 equiv) in DMF (13 mL) is heated to 80° C. for 2.5 h. The reaction mixture is allowed to cool to rt and concentrated in vacuo. The residue is diluted with EtOAc (25 mL) and H2O (66 mL). The layers are separated and the aqueous layer is extracted with EtOAc (2×40 mL and 2×50 mL). The organic phase is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel (80 g) column chromatography CH2Cl2/Et2O, 90/10). The title compound is obtained as a white solid: ES-MS: 327.0 [M+H]+; single peak at tR=7.42 min (System 2); Rf=0.26 (CH2Cl2/Et2O, 90/10).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[C:3]3[N:4]([CH:12]=[CH:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:18][CH2:17]1
Reactant: Clc1nc2ccccc2n2ccnc12
Reactant: CN1CCNCC1
Product: CN1CCN(c2nc3ccccc3n3ccnc23)CC1

Procedure:
By reaction of 4-chloroimidazo[1,2-a]quinoxaline (example 1) with N-methylpiperazine, according to a procedure that is similar to that followed in example 3, there is obtained 4-(N'-methylpiperazinyl)imidazo[1,2-a] quinoxaline. m.p. (DSC)=305.6° C.(onset); IR (KBr): 2697, 1560, 1508 cm-1 ; 1H-NMR (DMSO-d6 /CD3OD): δ8.7 (1H,sb), 8.3÷8.0 (1H,m), 7.8÷7.35 (4H,m), 5.5 (4H,t), 3.7÷3.3 (4H,m), 2.8 (3H,s); UV (EtOH): λmax =230, 291, 304, 320 nm. Elementary analysis for C15H17N5.2HCl (m.w. 340.25): calcd. C 52.95, H 5.63, N 20.58%; found C 52.81, H 5.78, N 20.13%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:21])[NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)[CH3:9])(C)(C)C.[ClH:23].O1CCOCC1>C(Cl)Cl>[ClH:23].[ClH:23].[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:14][CH2:13]1)=[O:21]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(c2ccccn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)NC1(c2ccccn2)CC1
Reaction time: 4 h

Procedure:
A solution of [(S)-1-(1-pyridin-2-yl-cyclopropylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (120 mg, 0.39 mmol) in CH2Cl2 (5 mL) was added 4M HCl in dioxane (0.98 mL, 3.9 mmol). The solution stirred for 4 hours then was concentrated in vacuo to afford crude (S)-2-amino-N-(1-pyridin-2-yl-cyclopropyl)-propionamide dihydrochloride (100 mg, 0.36 mmol).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:12]1[C:24]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH2:36])[C:31]([OH:33])=[O:32])=[O:28])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH:21]1[C:22]2[CH:23]([CH2:25][O:26][C:27]([NH:29][C@@H:30]([CH2:34][CH2:35][NH:36][C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])[C:31]([OH:33])=[O:32])=[O:28])[C:24]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=C(Cl)C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(N[C@@H](CCNC(=O)C1CCCCC1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclohexanecarbonyl chloride (86 mg, 0.588 mmol) and NaOH (0.705 mL, 0.705 mmol) were dropped at the same time to a stirred solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-aminobutanoic acid (200 mg, 0.588 mmol) in THF (1.5 mL) and of NaOH (1N, 0.7 mL) at 0° C. The reaction mixture was allowed to stir at rt for 1 h at which time LC-MS showed desired product peak. The reaction solution was acidified with 1N HCl and extracted with EtOAc (60 mL×1). The crude materials were purified via flash chromatography (ISCO, silica gel, 12 g column; flow rate 30 mL/min, 100% DCM to 20% MeOH/DCM). Fractions containing the desired product were combined and dried via centrifugal evaporation to provide the title compound (201 mg, 70%).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([C:25]4[C:26]5[N:27]([CH:44]=[CH:45][N:46]=5)[CH:28]=[C:29]([Sn](CCCC)(CCCC)CCCC)[N:30]=4)[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:2]1.[C:47]([O:51][C:52]([N:54]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:55]1[C:60]([Cl:61])=[N:59][CH:58]=[C:57](Br)[N:56]=1)=[O:53])([CH3:50])([CH3:49])[CH3:48]>O1CCOCC1.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>[C:47]([O:51][C:52]([N:54]([C:55]1[C:60]([Cl:61])=[N:59][CH:58]=[C:57]([C:29]2[N:30]=[C:25]([N:17]([C:18]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:24])[C:14]3[CH:15]=[CH:16][C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:3]5[CH2:2][O:1][CH2:4]5)[CH2:10][CH2:9]4)=[CH:12][CH:13]=3)[C:26]3[N:27]([CH:44]=[CH:45][N:46]=3)[CH:28]=2)[N:56]=1)[C:63](=[O:64])[O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:53])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)cnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2ccnc2c(N(C(=O)OC(C)(C)C)c2ccc(N3CCN(C4COC4)CC3)cc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2cn3ccnc3c(N(C(=O)OC(C)(C)C)c3ccc(N4CCN(C5COC5)CC4)cc3)n2)cnc1Cl

Procedure:
tert-Butyl 4-(4-(Oxetan-3-yl)piperazin-1-yl)phenyl(6-(tributylstannyl)imidazo[1,2-a]pyrazin-8-yl)carbamate V (1000 mg, 1.4 mmol), 2-Bis(tert-butoxycarbonyl)amino-6-bromo-3-chloropyrazine XI (552 mg, 1.35 mmol), and PdCl2(PPh3)2 (142.77 mg, 0.20 mmol), in 1,4-Dioxane (11.27 ml) was irridated in the microwave for 20 min at 140° C. The reaction was absorbed onto celite and eluted off a 40 g Gold Isco column using 0-10-100% (30% MeOH/DCM) over 20 column volumes. Fractions 34-39 were collected and concentrated. According to NMR, the title compound XII was identified and isolated.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH3:24].C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.[Pd].O1CCOCC1>[CH2:23]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[N:3]=[C:4]([C:9]3[O:10][C:11]([C:14]4[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=4)=[N:12][N:13]=3)[C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH3:24]
Reactant: CNCc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)cc1
Temperature: 150 °C
Yield: 59.5 %

Procedure:
To a 0.5-2.0 mL microwave vial 5-bromo-3-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (100 mg, 0.24 mmol), 4-(ethylsulfonyl)phenylboronic acid (56.72 mg, 0.265 mmol), dioxane (1 mL) and aqueous solution of Na2CO3 (361.3 μL of 2M solution, 0.72 mmol) were added. Palladium; triphenylphosphane (13.91 mg, 0.012 mmol) was then added and the vial sealed. The reaction mixture was heated in the microwave at 150° C. for 30 min. After this time the reaction mixture was diluted with DMSO (2 mL) and filtered before purification by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The product fractions were collected and evaporated to dryness to give the product as a yellow solid (64.35 mg, 65% yield); 1H NMR (400.0 MHz, DMSO) d 1.14 (t, 3H), 2.64 (s, 3H), 3.33-3.39 (m, 2H), 4.29 (s, 2H), 7.77 (d, 2H), 8.02 (d, 2H), 8.26 (d, 2H), 8.41 (d, 2H), 8.93 (s, 2H) and 9.09 (s, 1H) ppm; MS (ES+) 451.0
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:14]([C:18]1[CH:35]=[CH:34][C:21]([O:22][CH:23]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:24](O)=[O:25])=[CH:20][CH:19]=1)([CH2:16][CH3:17])[CH3:15]>>[CH3:13][S:12][C:11]1[C:2]([NH:1][C:24](=[O:25])[CH:23]([O:22][C:21]2[CH:34]=[CH:35][C:18]([CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:19][CH:20]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:3]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CSc1ccc2ncccc2c1N
Reactant: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)O
Product: CCCCCCCC(Oc1ccc(C(C)CC)cc1)C(=O)Nc1c(SC)ccc2ncccc12

Procedure:
5-Amino-6-methylthioquinoline, prepare as described in Example 34, was coupled with 2-(4-sec-butylphenoxy)nonanoic acid according to the procedure described in Example 25 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]#[CH:13])[C:6]=2[CH:14]=1.[C:15]1(=O)[O:20][C:18](=[O:19])[C:17]2[CH2:21][CH2:22][CH2:23][CH2:24][C:16]1=2.C(O)(=O)C>O>[CH2:11]([N:7]1[C:6]2[CH:14]=[C:2]([N:1]3[C:18](=[O:19])[C:17]4[CH2:21][CH2:22][CH2:23][CH2:24][C:16]=4[C:15]3=[O:20])[CH:3]=[CH:4][C:5]=2[O:9][C:8]1=[O:10])[C:12]#[CH:13]
Reactant: C#CCn1c(=O)oc2ccc(N)cc21
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: C#CCn1c(=O)oc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc21
Yield: 35 %

Procedure:
A mixture of 5-amino-3-(2-propynyl)-3H-benzoxazol-2-one (0.50 g), 3,4,5,6-tetrahydrophthalic anhydride (0.53 g) and acetic acid (5 ml) was heated at 100° to 110° C. under reflux for 3 hours. After being allowed to cool, water was added to the mixture, which was then extracted with ethyl acetate. The organic layer was washed with water, neuralized with sodium bicarbonate solution, dried and concentrated to give 2-[3-(2-propynyl)-3H-benzoxazol-2-on-5-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.30 g). m.p., 285.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].[CH3:10][CH:11]([OH:14])[CH:12]=[CH2:13].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[Cl:9][C:3]1[CH:4]=[C:5]([CH2:13][CH2:12][C:11](=[O:14])[CH3:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C=CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 88 %

Procedure:
A microwave vial was charged with palladium acetate (0.165 g, 0.733 mmol), 1,2-dichloro-4-iodobenzene (2.00 g, 7.33 mmol), but-3-en-2-ol (0.793 g, 11.0 mmol), tetrabutylammonium chloride, hydrate (2.17 g, 7.33 mmol), and sodium bicarbonate (1.539 g, 18.32 mmol). DMF (5 mL) was added via syringe and the reaction mixture was degassed three times. The mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool to rt, diluted with ether and the organic layer was washed with water. The organic layer was separated, dried with MgSO4, filtered and concentrated. The crude residue was purified by silica gel chromatography with an eluent of 10% ethyl acetate/hexanes to afford the desired product Intermediate 29A (1.40 g, 6.45 mmol, 88% yield). LC-MS (ESI) m/z 216.9 (M+H), RT=2.01 min (Method B).
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:16]=[C:17]([Br:20])[CH:18]=[CH:19][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cc(Br)ccc2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Brc1ccc2c(c1)CN(Cc1ccccc1)CCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
To a solution of 4-benzyl-7-bromo-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (4.20 g, 12.8 mmol) in tetrahydrofuran (400 ml) was added 1M borane-tetrahydrofuran solution (52.8 ml, 52.8 mmol) and the mixture was stirred at 80° C. for 2 hr. Under ice-cooling, methanol (240 ml) and sodium hydroxide (20.8 g, 519 mmol) were added, and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure. The residue was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (2.42 g, 59.5%) as an oil.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[CH3:32][NH:19][CH2:18][C@@H:17]([NH:16][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1)[C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:37][CH:38]=1
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CN(C[C@@H](N)c1ccc(C(F)(F)F)cc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(C(F)(F)F)cc1

Procedure:
Compound 38 was prepared following general synthesis scheme 8 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-trifluoromethyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [391 (M+H)]; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.21 (s, 1H), 9.00 (d, J=4.4 Hz, 1H), 8.52 (s, 1H), 8.38 (d, J=4.4 Hz, 1H), 8.17 (s, 1H), 7.68 (s, 4H), 5.53 (s, 1H), 3.20-3.07 (m, 1H), 2.94 (dd, J=12.2, 4.9 Hz, 1H), 2.30 (s, 3H).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]([NH:18][C:19]([C:21]1[S:25][CH:24]=[N:23][C:22]=1[CH3:26])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[I:27]I>O1CCCC1>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([I:27])=[N:23][C:22]=1[CH3:26])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: II
Reactant: Cc1ncsc1C(=O)NCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(I)sc1C(=O)NCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A solution of lithium hexamethyldisilazide (4.63 g, 27.65 mmol) in anhydrous tetrahydrofuran (25 mL) was added dropwise to a solution of N-benzyl-4-methylthiazole-5-carboxamide (2.79 g, 12.02 mmol) in anhydrous tetrahydrofuran (25 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred at −78° C. for 1 hour, then iodine (1.68 g, 13.22 mmol) was added in portions. The mixture was stirred at ambient temperature for 90 minutes, quenched with methanol (2 mL) and water (2 mL). The solvent was removed in vacuo and the residue was diluted with water (30 mL) and extracted with dichloromethane (3×40 mL). The organic layers were combined, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography (20-35% ethyl acetate in hexanes) to afford the title compound as a white solid (2.03 g, 47%): 1H NMR (300 MHz, CDCl3) δ 7.39-7.30 (m, 5H), 6.02 (br s, 1H), 4.57 (d, J=6.0 Hz, 2H), 2.68 (s, 3H); MS (ES+) m/z 359.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][N:6]=[CH:5]2.Cl.Cl.[CH:15]([N:18]1[CH2:23][CH:22]2[CH2:24][CH:19]1[CH2:20][NH:21]2)([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:21]1[CH2:20][CH:19]3[CH2:24][CH:22]1[CH2:23][N:18]3[CH:15]([CH3:17])[CH3:16])=[N:7][N:6]=[CH:5]2
Reactant: Clc1nncc2cc(Br)ccc12
Reactant: CC(C)N1CC2CC1CN2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)N1CC2CC1CN2c1nncc2cc(Br)ccc12
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 46.7 %

Procedure:
A mixture of 6-bromo-1-chlorophthalazine (Example 1, 90 mg, 370 μmol), 2-isopropyl-2,5-diaza-bicyclo[2.2.1]heptane dihydrochloride (95 mg, 444 μmol) and potassium carbonate (153 mg, 1109 μmol) in 10 mL acetonitrile was stirred at 130° C. under in a sealed tube. The mixture turned red in about 5 min. The reaction was monitored by MS. After about 1 h at 130° C., MS and TLC showed all starting material was converted to product (M+1=347, 349). The mixture was cooled down to room temperature, and concentrated on a Rotavaporator. After purification by column (eluting with gradient of 2-10% 2M ammonia in methanol to DCM), 2-(6-bromophthalazin-1-yl)-5-isopropyl-2,5-diaza-bicyclo[2.2.1]heptane (60 mg) was obtained as a yellow solid.