Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:11](C)[C@H:12]([C:16]([N:18]([CH3:39])[C@H:19]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])(OCC1C=CC=CC=1)=O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH:11]([CH3:1])[C@H:12]([C:16]([N:18]([CH3:39])[C@H:19]([C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[O:33])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([CH3:29])([CH3:30])[CH3:31])[CH:22]=1)=[O:17])[CH:13]([CH3:14])[CH3:15]
Reactant: [H][H]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)N(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(=O)NS(C)(=O)=O)C(C)C
Yield: 100.2 %

Procedure:
A mixture of Z-N-Me-Val-N-Me-Tyr(3-t-Bu)-NHSO2Me (0.65 g, 1.13 mmol) and 20% palladium hydroxide/carbon (0.09 g) in methanol (10 ml) was stirred at room temperature for 2.5 hours in a hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated to remove the solvent under reduced pressure, giving crude N-Me-Val-N-Me-Tyr(3-t-Bu)-NHSO2Me (0.50 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:11]([CH3:18])([CH3:17])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH3:16][O:15][CH2:14][CH2:13][N:12]1[C:4]2=[N:3][C:2]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:7][C:6](=[O:8])[N:5]2[CH2:9][CH2:10][C:11]1([CH3:18])[CH3:17]
Reactant: COCCN1c2nc(Cl)cc(=O)n2CCC1(C)C
Reactant: C1COCCN1
Product: COCCN1c2nc(N3CCOCC3)cc(=O)n2CCC1(C)C
Yield: 58 %

Procedure:
0.07 g of 2-chloro-9-(2-methoxyethyl)-8,8-dimethyl-6,7,8,9-tetrahydro-4H-pyrimido-[1,2-a]pyrimidin-4-one in 2.5 mL of morpholine are heated with the microwave oven to 80° C. for 2 h. The crude is purified by flash chromatography on silica gel SiO2 (100% CH2Cl2 to 92/8 CH2Cl2/MeOH). 0.050 g (yield=58%) of 9-(2-methoxyethyl)-8,8-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are obtained as a white solid including the following characteristics:
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccncc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccnc1Nc1ccncc1

Procedure:
The nitro compound from Step A (1.0 g.) was hydrogenated in 60 ml. of methanol over 0.2 g. of 5% palladium on carbon catalyst. The catalyst was removed by filtration and the filtrate was evaporated to dryness.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([CH:15]=[C:16]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:17]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[CH:21]1([C:19]([NH:18][C:16]2[N:17]=[C:12]3[CH:11]=[CH:10][C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)[CH:7]=[CH:6][CH:5]=4)=[N:14][N:13]3[CH:15]=2)=[O:20])[CH2:22][CH2:23]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Sc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 69.2 %

Procedure:
Using N-{6-[(3-aminophenyl)sulfanyl]imidazo[1,2-b]pyridazin-2-yl}cyclopropanecarboxamide (140 mg, 0.430 mmol), 3-(trifluoromethyl)benzoic acid (98 mg, 0.516 mmol), oxalyl chloride (75 μL, 0.860 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (148 mg, 75%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](Br)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.CN(C=O)C.[CH2:34]([N:41]1[CH:49]=[C:48]2[C:43]([CH:44]=[C:45](B3OC(C)(C)C(C)(C)O3)[CH:46]=[CH:47]2)=[N:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[NH2:1][C:2]1[C:7]2=[C:8]([C:45]3[CH:46]=[CH:47][C:48]4[C:43]([CH:44]=3)=[N:42][N:41]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:49]=4)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(c3cc(Br)c4c(N)ncnn34)OCC2C1
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
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+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 100 °C
Yield: 39 %

Procedure:
To a stirred solution of tert-butyl 3-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.50 g, 3.31 mmol) and tetrakis(triphenylphosphine)palladium(0) (764 mg, 0.66 mmol), in degassed 1,4-dioxane (15 mL) and DMF (15 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (1.33 g, 3.97 mmol), K2CO3 (1.10 g, 7.94 mmol), and H2O (3.9 mL). The mixture was degassed and heated (100° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (250 mL) and saturated aqueous K2CO3 solution (200 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was purified by recrystallization from acetonitrile to obtain 750 mg (39%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.71 (s, 1H), 5.64 (s, 2H), 5.14-5.10 (m, 1H), 3.88-3.71 (m, 3H), 3.33-3.26 (m, 2H), 3.03-2.99 (m, 1H), 2.89-2.69 (m, 2H), 2.42-2.38 (m, 1H), 2.12-2.08 (m, 2H), 1.38 (s, 9H); LC-MS [M+H]+=581, RT=2.57 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:8]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1cc(C(=O)O)cc2c1OCO2
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-methoxy-4,5-methylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])=[O:26]>>[Cl:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[CH2:28][O:27][C:25](=[O:26])[NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1
Reactant: O=C(Cl)OCc1ccccc1Cl
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)OCc4ccccc4Cl)nc3cc21

Procedure:
[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-carbamic acid 2-chloro-benzyl ester was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-chlorobenzyl chloroformate (135 μl, 0.89 mmol). The title compound was obtained as yellow powder (227 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.O=S(Cl)Cl.[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[CH:22]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C.ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][C:12]([C:22]1[C:23]([O:29][CH3:30])=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[O:20][CH3:19])=[O:14]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: COc1cc(OC)cc(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(CC(=O)c2c(OC)cc(OC)cc2OC)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.1 %

Procedure:
A solution of 2,4-dimethoxyphenyl acetic acid (7.9 g, 38 mmol) in CH2Cl2 (50 mL) plus a few drops of DMF was treated with SOCl2 (5.0 mL, 76 mmol) and the reaction was allowed to stir for 3 h at rt. The reaction mixture was then concentrated and taken up in a small amount of dichloroethane and added dropwise, at 0° C., to a solution of 1,3,5-trimethoxybenzene (12.8 g, 76 mmol) and AlCl3 (7.3 g, 57 mmol) in 50 mL dichloroethane. After 20 minutes at 0° C., the reaction was carefully quenched with 2 N HCl aq. The organic layer was separated, dried over MgSO4, filtered and concentrated to give a dark oil which was chromatographed on SiO2 (3:7 EtOAc/hexanes to 1:1 EtOAc/hexanes) to yield the desired product as a white solid (6.2 g): Mp 109-111° C.; 1H NMR (CDCl3) δ 7.06 (d, 1H, J=8.1 Hz), 6.41 (dd, 1H, J=8.1Hz, 2.4Hz), 6.39 (d, 1H, J=2.4Hz), 6.04 (s, 2H), 3.97 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 3.74 (s, 6H), 3.71 (s, 3H); MS FI 347 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][NH:7][C:6](=O)[C:5]=2[CH:4]=[C:3]1[CH3:16].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:6]1[C:5]2[CH:4]=[C:3]([CH3:16])[N:2]([CH3:1])[C:10]=2[C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1c[nH]c(=O)c2cc(C)n(C)c12
Product: COC(=O)c1cnc(Cl)c2cc(C)n(C)c12

Procedure:
A solution of methyl 1,2-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.311 g) in phosphorus oxychloride (7 ml) was heated under reflux for four hours, then evaporated under reduced pressure. The residual liquid was added to a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with a further portion of ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium bicarbonate and then water. After filtering the water and ethyl acetate mixture, the organic phase washed with brine, dried (MgSO4) and evaporated. Purification by chromatography on silica gel (ethyl acetate/toluene) afforded the title compound as a pale cream solid 1.027 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:25][C:26]1[C:31](B(O)O)=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:18])=[N:10]2)=[CH:3][C:2]=1[C:31]1[C:26]([F:25])=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2ccccc21
Reactant: OB(O)c1cccnc1F
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(-c3cccnc3F)c2)c2ccccc21

Procedure:
The title compound was synthesized from 1-(3-bromo-4-fluorophenyl)-1-pyridin-4-yl-1H-isoindol-3-amine (Scheme #11, G) as described in Example 67 Scheme #10, D using 2-fluoropyridine-3-boronic acid. 1H NMR (DMSO-d6) δ 8.49-8.41 (m, 2 H), 8.32-8.27 (m, 1 H), 8.04-7.95 (m, 1 H), 7.88-7.79 (m, 2 H), 7.55-7.40 (m, 5 H), 7.35-7.25 (m, 3 H), 6.92 (br s, 2 H); MS (ESI) m/z 399 [M+1]+.
Reaction SMILES: O=[C:2]1[CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:18][CH2:17][C:16](=O)[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[O:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:2][NH:3][CH2:4][CH2:5]1
Reactant: O=C1COCCOCCOCC(=O)NCCOCCOCCOCCN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1COCCOCCOCCNCCOCCOCCOCCN1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 30 g. of the diamide obtained in Example 15 in 200 ml. anhydrous tetrahydrofurane is slowly added to a mixture of 50 ml. anhydrous tetrahyfrofurane and 18 g. LiAlH4 while stirring and heating at the reflux temperature. After the addition is completed, the mixture is stirred under reflux and under a nitrogen atmosphere for 24 hours. After cooling to room temperature the reducing agent is destroyed by adding a mixture of water and THF (1:2). The mixture is filtered and the filtrate is evaporated to dryness. The residue is dissolved in benzene and the solution is passed through a column of Al2O3 with benzene as eluant. The solution is evaporated to dryness and the desired product is obtained as a colourless oil which crystallizes at low temperatures.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2([CH2:46][CH2:45]2)[C:37]1=[O:47].[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CO.ClCCl>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:33][CH2:34][CH2:35][N:36]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[C:38]4([CH2:46][CH2:45]4)[C:37]3=[O:47])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: O=C1N(CCCCl)c2ccccc2C12CC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Yield: 72 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate) (0.25 g, 0.593 mmol), 1′-(3-chloropropyl)spiro[cyclopropane-1,3′-indolin]-2′-one) (0.14 g, 0.593 mol), sodium iodide (0.027 g, 0.178 mmol), and potassium carbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were heated at 78° C. for 4 hours. The reaction was diluted with 10% methanol/dichloromethane, filtered, and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as a white solid (0.27 g, 72%); 1H NMR (DMSO-d6); δ1.51 (s, 9H); 1.53-1.63 (m, 6H); 1.80 (m, 2H); 2.37 (m, 2H); 2.51-2.63 (m, 2H); 2.63-2.76 (m, 4H); 3.82 (t, J=6.8 Hz, 2H); 4.58 (s, 2H); 4.61 (s, 2H); 6.76 (t, J=7.2 Hz, 1H); 6.85 (d, J=8.4 Hz, 2H); 6.98-7.00 (m, 2H); 7.19-7.24 (m, 4H); 7.49-7.56 (m, 2H); 7.79 (s, 1H); 7.82-7.84 9M, 1H); MS for C38H44N4O4 m/z 621 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[CH2:18][C:12]3(N3CCCC3)[O:11][N:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.O.S(=O)(=O)(O)O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH2:14][CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[CH2:18][C:12]=3[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCCC2C(c3ccc(C(F)(F)F)cc3)=NOC2(N2CCCC2)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CCCc2c(-c3ccc(C(F)(F)F)cc3)noc2C1
Temperature: 120 °C
Yield: 11.9 %

Procedure:
3.38 g of methyl 3-(4-trifluoromethylphenyl)-3a,5,6,7,8,8a-hexahydro-8a-pyrrolidino-4H-cyclohept[d]isoxazole-7-carboxylate were dissolved in a mixture of 10 ml of glacial acetic acid, 10 ml of water and 10 ml of concentrated sulfuric acid and heated at 120° C. for 2 hours. The mixture was cooled, diluted with water and extracted three times with 100 ml of methylene chloride each time. The extracts were dried over magnesium sulfate and evaporated and the residue was crystallized from methanol to give 0.32 g of 3-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylic acid of melting point 222°-225° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[NH:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1>CN(C=O)C.O>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][N:43]5[CH2:47][CH2:46][CH2:45][CH2:44]5)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(-c3cccc(CCl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnn2c(-c3cccc(CN4CCCC4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 1 h
Yield: 44.7 %

Procedure:
The product from step 1 (60 mg, 0.13 mmol) was dissolved in 1 mL of DMF and K3PO4 (33 mg, 0.16 mmol) was added. The mixture was treated with pyrrolidine (0.15 mL, 1.55 mmol) and stirred for 1 hour. The mixture was diluted with water (10 mL) and stirred for 10 minutes. The precipitate was collected and purified by preparative HPLC eluting with 10%-90% acetonitrile/water (0.1% TFA) to provide 29 mg (54%) of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:53]=[CH:52][C:19]([CH2:20][CH2:21][NH:22][CH2:23][C@H:24]([OH:51])[CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)=[CH:29][CH:28]=3)=[CH:18][CH:17]=2)=[O:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.[Cl-].[NH4+]>[CH2:1]([C:8]1[O:12][N:11]=[C:10]([CH2:13][S:14]([C:16]2[CH:53]=[CH:52][C:19]([CH2:20][CH2:21][NH:22][CH2:23][C@H:24]([OH:51])[CH2:25][O:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)=[CH:18][CH:17]=2)=[O:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(S(=O)Cc3noc(Cc4ccccc4)n3)cc2)cc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: O=S(Cc1noc(Cc2ccccc2)n1)c1ccc(CCNC[C@H](O)COc2ccc(O)cc2)cc1
Reaction time: 6 h
Yield: 64.6 %

Procedure:
To a solution of the amino alcohol of Example 23 (0.490 g, 0.643 mmol) in THF (10 mL) was added a 1M solution of TBAF (0.13 mL, 0.13 mmol). The reaction mixture was stirred for 6 h. TLC shows the absence of starting material, so 3 drops of a saturated aqueous ammonium chloride solution was added. The reaction mixture was evaporated in vacuo to dryness and the residue was flash chromatographed (silica gel; dichloromethane/chloroform/methanol: 5/4/1) to afford 0.211 g of the title compound as a white crystalline solid. MP=51-57° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:13]=[CH:14]/[C:15]1[N:16]=[C:17]2[N:21]([C:22]=1[C:23]([OH:25])=O)[CH:20]=[CH:19][S:18]2.[NH2:28][C:29]1[S:30][CH:31]=[C:32]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][CH:35]=2)[N:33]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl.CN(C=O)C>[C:38]([C:37]1[CH:36]=[CH:35][C:34]([C:32]2[N:33]=[C:29]([NH:28][C:23]([C:22]3[N:21]4[C:17]([S:18][CH:19]=[CH:20]4)=[N:16][C:15]=3/[CH:14]=[CH:13]/[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=3[O:4][CH2:3][C:2]([CH3:27])([CH3:1])[CH3:26])=[O:25])[S:30][CH:31]=2)=[CH:41][CH:40]=1)#[N:39]
Reactant: N#Cc1ccc(-c2csc(N)n2)cc1
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)Nc2nc(-c3ccc(C#N)cc3)cs2)c1OCC(C)(C)C

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 3 (130 mg, 0.336 mmol) with 4-(2-amino-1,3-thiazol-4-yl)benzonitrile (81 mg, 0.403 mmol) in the presence of EDCI hydrochloride (128 mg, 0.672 mmol) and DMAP (61 mg, 0.504 mmol) in a mixture of DCM and DMF (4:1, 5 mL) to give 27 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (s, 9H), 3.57 (s, 2H), 3.80 (s, 3H), 7.00 (d, J=8.4 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.40-7.50 (m, 2H), 7.84 (s, 1H), 7.91-7.96 (m, 2H), 7.98-8.05 (m, 1H), 8.10-8.15 (m, 2H), 12.79 (br s, 1H); APCI-MS (m/z) 570.17 (MH)+.