Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:13][O:14][C:15]([N:17]1[CH:22]=[C:21]([O:23]C(=O)C)[CH:20]([CH3:27])[CH2:19][CH2:18]1)=[O:16]>CO>[CH3:13][O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([CH3:27])[C:21](=[O:23])[CH2:22]1)=[O:16]
Reactant: COC(=O)N1C=C(OC(C)=O)C(C)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)N1CCC(C)C(=O)C1
Yield: 32 %

Procedure:
In a 1000 ml round bottom flask, 50 g of crude 5-acetoxy-4-methyl-3,4-dihydro-2H-pyridine-1-carboxylic acid methyl ester was dissolved in 200 ml of methanol. To 300 ml water was added 30 g of sodium carbonate and 30 g sodium bicarbonate (pH=10). The aqueous buffer was added to the methanol solution. Methanol was added to the mixture until it stirred easily, and stirred at room temperature for 18 hours. The mixture was then concentrated to remove methanol. Water was added to the mixture to dissolve all salts. This was then extracted with ethyl acetate three times. The organic extracts were combined, dried over magnesium sulfate, filtered, and evaporated to furnish the crude compound 4-Methyl-3-oxo-piperidine-1-carboxylic acid methyl ester as oil, which was then purified as described below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][CH2:23][CH2:24]I)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:26]([Si:30]([CH3:47])([CH3:46])[O:31][C@H:32]1[C@@H:37]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35][NH:34][CH2:33]1)([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CC(N(C)C)=O>[C:26]([Si:30]([CH3:47])([CH3:46])[O:31][CH:32]1[CH:37]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[CH2:36][CH2:35][N:34]([CH2:24][CH2:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:14][CH2:15]2)[CH2:33]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCI)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCN(CCCCN2CCN(C(=O)/C=C/c3ccc(Cl)c(Cl)c3)CCC2=O)CC1O[Si](C)(C)C(C)(C)C
Reaction time: 2.25 h
Yield: 75.1 %

Procedure:
A solution of 0.279 g (0.56 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) in 2 ml of DMA was treated with 0.195 ml (0.56 mmol) of (cis)-(rac)-3,4-Bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 25) and 0.184 g (0.56 mmol) of cesium carbonate. After 2.25 h at RT, CH2Cl2 was added, filtrated and evaporated. Purification by catridges, Si-Amine, 50 g, (EtOAc/n-heptane 4:1) gave 0.300 g (75%) of the title compound as light brown foam. MS: 712.6 (MH+, 2Cl).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]12([CH2:38][NH:39][C:40]([C:42]3[C:43]4[N:44]([N:48]=[C:49]([C:51](O)=[O:52])[CH:50]=4)[CH:45]=[CH:46][CH:47]=3)=[O:41])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2.[NH:54]1[CH2:58][CH2:57][C@@H:56]([NH:59][C:60](=[O:66])[O:61][C:62]([CH3:65])([CH3:64])[CH3:63])[CH2:55]1.CN(C=O)C>CCOC(C)=O>[C:62]([O:61][C:60](=[O:66])[NH:59][C@@H:56]1[CH2:57][CH2:58][N:54]([C:51]([C:49]2[CH:50]=[C:43]3[C:42]([C:40](=[O:41])[NH:39][CH2:38][C:28]45[CH2:37][CH:32]6[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]6)[CH2:29]4)[CH2:35]5)=[CH:47][CH:46]=[CH:45][N:44]3[N:48]=2)=[O:52])[CH2:55]1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: O=C(O)c1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)c2cc3c(C(=O)NCC45CC6CC(CC(C6)C4)C5)cccn3n2)C1
Reaction time: 20 h

Procedure:
BOP (680 mg, 1.5 mmol) is added to a mixture of 4-[(adamantan-1-ylmethyl)carbamoyl]-pyrazolo[1,5-a]pyridine-2-carboxylic acid (417 mg, 1.18 mmol), tert-butyl (R)-pyrrolidin-3-ylcarbamate (242 mg, 1.30 mmol), iPr2Net (620 μL, 3.6 mmol) and DMF (12 mL) under N2. The reaction vessel is sealed and the solution is left to stir for 20 h. EtOAc (50 mL) is added. The solution is washed with H2O (2×50 mL) and brine (50 mL). The organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (2% MeOH in CH2Cl2) affords (R)-(1-{4-[(adamantan-1-ylmethyl)carbamoyl]pyrazolo[1,5-a]-pyridine-2-carbonyl}pyrrolidin-3-yl)carbamic acid tert-butyl ester as a tan solid. MeOH (6.8 mL) and 4 M HCl in dioxane (1.7 mL) are added. After 20 h, the volatiles are removed under reduced pressure to afford a light tan solid. 15% Aqueous K2CO3 (50 mL) is added. The solution is extracted with EtOAc (5×50 mL). The combined organics are dried over Na2SO4, filtered, and concentrated. Purification by flash column chromatography (1% NH4OH in 9:1 CH2Cl2:MeOH) affords the title compound as a tan foam. 1H NMR (300 MHz, CDCl3) δ: 8.48 (ddd, 1H), 7.62 (dd, 1H), 7.22 (dd, 1H), 6.87 (t, 1H), 6.50 (bt, 1H), 3.42-4.20 (m, 5H), 3.20 (d, 2H), 2.14 (septet, 1H), 1.96-2.04 (m, 3H), 1.55-1.88 (m, 12H). LC-MS m/z (M+H+): 422.3; RT=1.2 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[OH-].[Na+].[CH2:18](Cl)Cl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[N+:1]([CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[C-:18]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: [C-]#[N+]CC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
To a solution of 4-aminomethyl-1-Boc-piperidine (77.1 g, 360 mmol, 1 equiv) in 108 mL of methylene chloride at room temperature (rt) was added benzyltriethylammonium chloride (1.64 g, 72 mmol, 0.2 equiv) followed by 108 mL of a 50% sodium hydroxide solution. The reaction spontaneously achieved a mild reflux for 1.5 h and was allowed to stir for an additional 12 h at rt. The reaction was diluted with H2O and the product was extracted into methylene chloride. The organic layer was dried over anhydrous potassium carbonate, filtered, and concentrated. The crude residue was passed through a pad of silica gel with a 2:1 EtOAc:hexane solution. Evaporation of the eluent provided 28.0 g (35%) the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[C:8]#[N:9].S(=O)(=O)(O)[OH:11]>>[Cl:7][C:4]1[C:3]([C:8]([NH2:9])=[O:11])=[C:2]([Cl:1])[S:6][N:5]=1
Reactant: N#Cc1c(Cl)nsc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(Cl)nsc1Cl
Temperature: 110 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed dichloro-1,2-thiazole-4-carbonitrile (3.7 g, 20.67 mmol, 1.00 equiv), sulfuric acid (15 mL). The resulting solution was stirred for 2 h at 110° C. The solution was used for the next step directly.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.C1(=O)OC(=O)CC1>>[C:1]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(O)CC1
Agent: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@H]1CC[C@@H](O)CC1

Procedure:
1 g 4-tert.-Butyl-cyclohexanol (cis/trans 30:70; i.e. 1 eq) was mixed with 10 ml toluene (i.e. 0.6 mol). 0.5 g succinic anhydride (i.e. 0.8 eq) and 0.1 g lipase immobilized on Na2SO4 were added (i.e. 10% per weight). The reaction conditions were the same as in example 1.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].C([C:22]1[C:27]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O)(C)(C)C>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[S:28](=[O:30])(=[O:31])[NH:29][C:3]([CH3:13])([CH3:4])[CH3:2])=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(C)(C)c1c(B(O)O)cccc1S(N)(=O)=O
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1cnc(N)c(C(=O)Nc2ccncc2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 2-tert.-butyl-sulfamoyl-benzeneboronic acid gives “A64”; method 1: HPLC/MS: 1.41 min, [M+H]=426;
Reaction SMILES: C([O:8][C:9]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=2)O)=[C:13]([CH3:25])[CH:12]=[C:11]([CH3:26])[N:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH2:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:15][C:14]2[C:9](=[O:8])[NH:10][C:11]([CH3:26])=[CH:12][C:13]=2[CH3:25])=[CH:22][CH:21]=1)[CH3:24]
Reactant: CCc1ccc(C(O)c2c(C)cc(C)nc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Cc2c(C)cc(C)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92 %

Procedure:
To a solution of 3-cyano-4,6-dimethyl-1H-pyridin-2-one (4.6 g) in dichloromethane (150 mL) were added benzyl bromide (5.6 mL) and silver carbonate (26 g), and the mixture was stirred under shading for 3 hours at 50° C. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=7/1) to give 2-benzyloxy-3-cyano-4,6-dimethylpyridine (7.1 g). To diisobutylaluminum hydride (1.5 mol/L solution in toluene, 8.7 mL) was added a solution of 2-benzyloxy-3-cyano-4,6-dimethylpyridine (2.4 g) in tetrahydrofuran (4.3 mL) at 0° C., and the mixture was stirred for 4 hours at 0° C. The reaction mixture was poured into 1 mol/L hydrochloric acid solution (40 mL), and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=50/1-20/1-10/1) to give 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.90 g). To a solution of 4-ethylbromobenzene (0.044 g) in tetrahydrofuran (1.2 mL) was added tert-butyllithium (1.5 mol/L solution in hexane, 0.17 mL) at −78° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. A solution of 2-benzyloxy-3-formyl-4,6-dimethylpyridine (0.048 g) in tetrahydrofuran (1.3 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes for 0° C. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with diethylether. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=5/1) to give 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.066 g). To a solution of the obtained 2-benzyloxy-4,6-dimethylpyridin-3-yl-4-ethylphenylmethanol (0.061 g) in ethanol (3.5 mL) was added 10% palladium carbon powder (0.037 g), and the mixture was stirred for 12 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloro-methane/methanol=10/1) to give 3-(4-ethylbenzyl)-4,6-dimethyl-1H-pyridin-2-one (0.039 g).
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[S:8][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[NH:6][C:4]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C(#N)C>[CH2:2]([CH:3]1[C:4](=[S:24])[NH:6][C:7]2([CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[S:8]1)[CH3:1]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC1SC2(CCN(C)CC2)NC1=O
Solvent: CC#N
Product: CCC1SC2(CCN(C)CC2)NC1=S

Procedure:
A mixture of AF267 (214 mg, 1 mmol) and Lawesson's Reagent (280 mg, 0.692 mmol) in acetonitrile (5 ml) was heated under reflux for 17 hrs. The solvent was removed and residue was dissolved in concentrate aqueous sodium carbonate (0.5 ml) and then extracted with ethyl acetate. The extract was dried and the solvent evaporated. The residue (250 mg), recrystallized first from toluene and then from acetonitrile gave pure AF510. 1H-NMR (CDCl3) δ 1.03 (t, CH3CH2), 1.83 (m), 1.93–2.44 (m), 2.30 (s, CH3N), 2.80 (m, 2H), 4.21 (dd, SCH), 8.66 (br, NH) ppm. MS m/e 230 (M30), 197 (M+−SH), 156, 128, 96 (100%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[N+:23]([O-:25])=[O:24])[C:16]([O:18][CH3:19])=[O:17])=[O:11]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 5-liter four-necked round-bottomed flask 1.5 l of methylene chloride was cooled to -78° C. Oxalyl chloride (164 g, 1.29 moles) was added slowly, followed by dropwise addition of 202 g (2.59 moles) of dry dimethylsulfoxide in 125 mL of methylene chloride, keeping the temperature below -70° C. After the addition was complete the reaction mixture was stirred at -78° C. for 30 minutes and 273 g (1.29 moles) of previously prepared methyl 3-hydroxymethyl-4-nitrobenzoate dissolved in 250 mL of methylene chloride was added dropwise. The reaction mixture was stirred an additional 30 minutes. Triethylamine (392 g 3.88 moles) in 125 mL of methylene chloride was added dropwise keeping the temperature below -65° C. The reaction mixture was warmed up slowly to room temperature and stirred overnight. The solvent was removed using a rotary evaporator and the resulting solid treated with a mixture of 2 l of ethyl acetate and 1 l of water. The organic phase was separated, filtered through diatomaceous earth, and washed sequentially with dilute aqueous hydrochloric acid (2×250 mL), water (2×250 mL), saturated aqueous sodium bicarbonate (2×250 mL), water (2×200 mL), brine (1×200 mL) and dried over anhydrous magnesium sulfate. The solvent was removed using a rotary evaporator. The crude reaction mixture was triturated with hexane and filtered yielding 234.1 g of the expected methyl 3-formyl-4-nitrobenzoate as a yellow solid. This compound was used as such in the next step.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[Si:9]([O:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C1COCC1>[Si:9]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22](=[O:23])[CH2:2][C:1]#[N:3])=[CH:25][CH:26]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC#N
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)CC#N)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
To a chilled (−78° C.) solution of acetonitrile (MeCN) (1.13 mL, 4 equiv) in THF (54 mL) was added butyllithium (BuLi) (1.62 mL, 10 M in hexanes, 3 equiv) dropwise, keeping the temperature under −60° C. The mixture was stirred for 15 minutes at −78° C. A solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)benzoyl chloride (1.44 g) in THF (5 mL) was slowly added, and the reaction mixture was stirred at −78° C. for 45 minutes. The reaction was then quenched with aqueous ammonium chloride and diluted with EtOAc. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate, and concentrated onto silica gel. Purification by silica chromatography (9:1 hexanes:EtOAc to EtOAc) provided the title compound (370 mg, 24% yield) and the de-silylated product (330 mg).
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][CH:10]=1
Reactant: C1COCCN1
Reactant: O=Cc1cc(Br)cs1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Sodium cyanoborohydride (2 g) was added portionwise to a stirred mixture of 4-bromo-2-thiophenecarbaldehyde (4.78 g), morpholine (2.1 g), glacial acetic acid (1.8 g) and ethanol (125 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic phase was washed with brine and evaporated. The resultant oil was partitioned between a dilute (10%) aqueous hydrochloric acid solution and methylene chloride. The aqueous phase was basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated to give 4-bromo-2-morpholinomethylthiophene (3.2 g);
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[N:20]=[C:21]([Cl:32])[N:22]=[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[C:24]=4[N:25]=3)[CH2:13]2)C1)=O)(C)(C)C.C1NC[CH2:36][N:35]2[CH2:39][CH2:40][CH2:41][C@@H:34]12>>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:24]2[N:25]=[C:17]([CH2:16][N:12]3[CH2:11][CH2:36][N:35]4[CH2:39][CH2:40][CH2:41][C@H:34]4[CH2:13]3)[S:18][C:19]=2[N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)CC2C1
Reactant: C1C[C@H]2CNCCN2C1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CCN4CCC[C@H]4C3)sc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using (S)-octahydro-pyrrolo[1,2-a]pyrazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a white solid (34 mg, 43%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[C:10]([CH3:19])([CH3:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1([CH2:26][N:27]=[C:28]=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([CH2:26][NH:27][C:28](=[O:29])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C=NCC1CCCCC1
Reactant: CC1(C)CN(Cc2ccccc2)c2ccc(O)cc21
Product: CC1(C)CN(Cc2ccccc2)c2ccc(OC(=O)NCC3CCCCC3)cc21

Procedure:
The title compound was synthesized from 1-benzyl-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with cyclohexylmethylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (10.5 mg, 34%) having the following characteristics.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[P:11]([O:15][CH3:16])([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[C:21]([O:20][C:18]([NH:17][CH:10]([P:11]([O:15][CH3:16])([O:13][CH3:14])=[O:12])[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][CH:6]=1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)c1ccc(C(NC(=O)OC(C)(C)C)P(=O)(OC)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COP(=O)(OC)C(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-[tert-Butoxycarbonylamino-(dimethoxy-phosphoryl)-methyl]-benzoic acid methyl ester (150 mg, 0.402 mmol) was made 0.25 M in dioxane and to this stirring solution was added 3 M aq LiOH (29 mg, 1.205 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was diluted with EtOAc and washed with 1N aq HCl. The organic layer was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was carried onto subsequent coupling without further purification: 1H NMR (DMSO-d6, 600 MHz) 12.68 (br-s, 1H), 8.07-8.13 (m, 1H), 7.84-7.92 (m, 2H), 7.50-7.61 (m, 2H), 5.15-5.25 (m, 1H), 3.46-3.63 (m, 6H), 1.36 (s, 9H).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9][C:8]=2[CH:17]=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9][C:8]=2[CH2:17][OH:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CC1=C(c2ccccc2)c2ccccc2CO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCC1=C(c2ccccc2)c2ccccc2CO1

Procedure:
4-phenyl-1H-isochromene-3-carbaldehyde (Intermediate G21, 410 mg, 1.735 mmol) suspended in MeOH (1 ml) was added dropwise to a solution of sodium tetrahydroborate (65.7 mg, 1.735 mmol) in MeOH (17.3 ml) at RT. The mixture was partitioned between AcOEt/NH4Cl 5% (2 ml/2 ml), the organic phase was separated, anhydrified over Na2SO4 and evaporated in vacuo to give a crude that underwent next step without any further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]3[C:18]([CH2:19][C:20](=[O:44])[N:21]([CH2:29][C:30]([N:32]([CH:41]([CH3:43])[CH3:42])[C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:31])[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=43)=[N:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:45]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[C:47]([CH:54]=O)=[CH:46]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:24]3[C:18]([C:19](=[CH:54][C:47]4[C:48]5[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=5)[NH:45][CH:46]=4)[C:20](=[O:44])[N:21]([CH2:29][C:30]([N:32]([CH:41]([CH3:42])[CH3:43])[C:33]4[CH:34]=[N:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=4)=[O:31])[C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=43)=[N:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: COc1ccc(N(C(=O)CN2C(=O)Cc3nnc(-c4cccc(OCc5ccccc5)c4)n3-c3ccccc32)C(C)C)cn1
Product: COc1ccc(N(C(=O)CN2C(=O)C(=Cc3c[nH]c4ccccc34)c3nnc(-c4cccc(OCc5ccccc5)c4)n3-c3ccccc32)C(C)C)cn1
Yield: 38.3 %

Procedure:
Following the procedure described for Example 1 (A), Step A, 2-[1-(3-benzyloxy-phenyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide (Preparation 6) (129 mg, 0.219 mmol) was condensed with 1H-indole-3-carbaldehyde (70 mg, 0.48 mmol). Purification by medium pressure chromatography eluting with a solvent gradient (10% EtOAc in hexanes to 100% EtOAc) yielded 60 mg of 2-[1-(3-benzyloxy-phenyl)-4-(1H-indol-3-ylmethylene)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-(6-methoxy-pyridin-3-yl)-acetamide. 1H NMR (CD3OD) δ 8.13 (m, 1H), 7.64 (m, 2H), 7.23-7.48 (m, 13H), 7.13 (m, 3H), 6.93 (m, 2H), 4.94 (m, 2H), 4.85 (m, 1H), 4.63 (m, 1H), 4.20-4.40 (m, 1H), 3.96 (m, 1H), 3.85 (d, 1H), 0.90-1.05 (m, 6H); MS 716.5 (M+1), 714.6 (M−1)