Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[C:17]([Si:21](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:20])([CH3:19])[CH3:18]>ClCCl>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][Si:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:17]([CH3:20])([CH3:18])[CH3:19])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.2 %

Procedure:
To a solution of ((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methan-1-ol (9 g, 68.6 mmol) in anhydrous dichloromethane (40 mL) were added triethylamine (11.2 mL), tert-butylchlorodiphenylsilane (19.8 g, 372 mmol), and N,N-dimethylaminopyridine (DMAP, 418 mg, 3.4 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight. It was then diluted with additional dichloromethane and the reaction mixture was washed with water, brine, dried over sodium sulfate, filtered and evaporated to give the title compound (27 g) which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: OB(O)c1cccnc1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine (Example 153) was reacted with pyridine-3-boronic acid via General Procedure E to give, after purification by reverse HPLC, 14 mg of 224. MS (Q1) 459 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:9]=2)=[CH:4][CH:3]=1.BrCCCN1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2C1=O>>[CH2:31]([O:32][C:16]([NH:15][CH2:14][CH2:10][CH2:9][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH:9]=2)=[CH:6][CH:7]=1)=[O:17])[C:30]1[CH:29]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(O)cc2)c1
Product: CC(C)(C)OC(=O)NCc1cccc(-c2ccc(OCCCNC(=O)OCc3ccccc3)cc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 31 using tert-butyl N-(4′-hydroxybiphenyl-3-ylmethyl)carbamate instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and N-(3-bromopropyl)phthalimide instead of N-(4-bromobutyl)-phthalimide.
Reaction SMILES: [F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3.[C:23](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[F:1][C:2]1[C:21]([I:22])=[CH:20][C:5]2[C:6]3[N:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]([CH3:23])[C:7]=3[CH:16]3[CH2:19][CH:18]([C:4]=2[CH:3]=1)[CH2:17]3
Reactant: CCOC(=O)c1nc2c([nH]1)C1CC(C1)c1cc(F)c(I)cc1-2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1nc2c(n1C)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 40 °C
Yield: 94.1 %

Procedure:
To a pressure tube containing a solution of ethyl 8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (400 mg at 69% purity) in N,N-dimethylformamide (0.5 mL) was introduced potassium carbonate (134 mg, 0.97 mmol) and methyl iodide (207 mg, 1.46 mol). The pressure tube was closed under an atmosphere of nitrogen and the reaction mixture warmed to 40° C. for 2.5 hr and room temperature for 12 hr. After concentrating the reaction mixture in vacuo, the residue was suspended in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2×10 m), water (2×10 ml) and brine (10 mL). The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo to furnish the crude title compound (389 mg of 77% purity LCMS-UV215) as an orange-brown sticky solid which was used for the next step without further purification. For characterisation purposes, some of the crude product was taken and suspended in ethyl acetate by sonnication and the product, an off-white solid, collected by filtration: 1H NMR (500 MHz, CDCl3) δ 1.48 (t, J=7.09 Hz, 3H), 1.69-1.74 (m, 2H), 2.92-3.00 (m, 2H), 3.50 (td, J=7.57, 3.78 Hz, 1H), 3.56 (td, J=8.35, 3.78 Hz, 1H), 3.94 (s, 3H), 4.46 (q, J=7.15 Hz, 2H), 6.79 (d, J=8.83 Hz, 1H), 8.83 (d, J=6.62 Hz, 1H); M+1=427.
Reaction SMILES: [Mg:1].[CH2:2]([OH:5])[CH2:3][CH3:4]>II>[O-:5][CH2:2][CH2:3][CH3:4].[Mg+2:1].[O-:5][CH2:2][CH2:3][CH3:4]
Reactant: [Mg]
Reactant: CCCO
Agent: II
Product: CCC[O-]
Product: [Mg+2]
Reaction time: 4 h
Yield: 93.9 %

Procedure:
Magnesium (3 g, 0.123 mole, 2 molar equiv.) was added to technical 1-propanol (100 ml) and the mixture was heated to reflux under nitrogen atmosphere. Then, sublimed iodine (0.2 g) as catalyst was added and the reflux was continued for 4 hours to obtain magnesium propoxide. Indazole-3-carboxylic acid (10 g, 0.0617 mole) was then added and the reflux was continued for 2 hours. Dimethyl sulfate (13.3 g, 10 ml, 0.105 mole, 1.7 molar equiv.) was added dropwise under reflux for 2 hours and the reflux was continued for a further 3 hours (the composition of the reaction mixture by HPLC was: 97.09% 1-MICA, 0.37% 2-MICA, and 2.54% ICA). The mixture was kept at room temperature overnight (the composition of the reaction mixture by HPLC was: 97.61% 1-MICA, 0.19% 2-MICA, and 2.21% ICA). Water (100 ml) and 46% aqueous sodium hydroxide solution were added to the reaction mixture to produce-pH of about 14. Then, conc. hydrochloric acid was added to the suspension to produce pH of about 4 and obtain a solution. The 1-propanol was removed under reduced pressure from the solution. The residuary mixture was stirred for 6 hours with a control of pH of about 4. The solid product was collected by filtration, washed with water (3×30 ml), and dried in oven at 50° C. overnight to give crude 1-MICA (10.2 g, 93.9% yield, purity by HPLC: 98.73%). The crude compound (10.2 g) was treated by slurry at heating under reflux in methanol-water (3:7) mixture (31 ml) for 4 hours. The precipitate was collected by filtration after cooling the mixture to room temperature, washed with methanol-water (3:7) mixture (3×10 ml), and dried in oven at 50° C. overnight to prepare pure 1-MICA (9.1 g, 83.8% yield, purity by HPLC: 99.71%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([NH:7][N:8]=[C:9]([C:11]1[C:15]([OH:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[S:13][CH:12]=1)[CH3:10])=[O:6].CC(C)([O-])C.[Na+].C1N=CN([C:40](N2C=NC=C2)=[S:41])C=1.Cl>O1CCCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:14]2[S:13][CH:12]=[C:11]([C:9](=[N:8][NH:7][C:5]([C:4]3[CH:25]=[CH:26][C:27]4[NH:28][C:40](=[S:41])[NH:1][C:2]=4[CH:3]=3)=[O:6])[CH3:10])[C:15]=2[OH:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(=NNC(=O)c1ccc(N)c(N)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc2[nH]c(=S)[nH]c2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
To a suspension of 3,4-diamino-N′-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl}ethylidene]benzohydrazide (30 mg, 0.064 mmol, see the synthetic example 176) in tetrahydrofuran (3.0 mL) was added sodium tert-butoxide (12 mg, 0.13 mmol) and N,N′-thiocarbonyldiimidazole (23 mg, 0.13 mmol). The reaction mixture turned clear orange and was stirred at room temperature for 16 hours, and then was acidified with 1M aqueous HCl solution (1.0 mL) and concentrated under the reduced pressure. The precipitated solid was collected by filtration, washed with chloroform, washed with methanol and dried by means of a vacuum pump to give the desired product as a pale brown solid (yield 52%).
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[CH:19]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])OCC.C(=O)(O)[O-].[Na+]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl.C(O)C>[CH2:27]([O:26][CH:19]([O:23][CH2:24][CH3:25])[CH:4]([N+:1]([O-:3])=[O:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:28]
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: CCOC(OCC)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C(OCC)OCC)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
Ethyl nitroacetate (1.70 ml, 15.31 mmol) was dissolved in dichloromethane (50 ml). Mixture was cooled to −10° C. Titanium(IV) chloride (1.90 ml, 17.23 mmol) was added to the mixture drop-wise. Mixture was held at −10° C. with stirring for 15 minutes. A solution of N,N-diisopropylethylamine (3.0 ml, 17.22 mmol) in 10 mL dichloromethane was added to the mixture drop-wise over 25 minutes. Mixture was held at −10° C. with stirring for 1.25 hours. Triethyl orthoformate (6.4 ml, 38.5 mmol) was added to the mixture drop-wise. Reaction was held at −10° C. with stirring for 2 hours. Reaction mixture was poured into a mixture of 40 mL ethanol and 100 mL aqueous sodium bicarbonate to quench. Mixture was stirred vigorously for 10 minutes. Organic solvents were removed from the mixture by roto-vap. Residue was treated with ethyl acetate and celite. Slurry was filtered over celite. Filtrate layers were separated. Aqueous phase was back extracted twice with ethyl acetate. Organic phases were combined. Material was dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as yellow oil in 68% yield. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 5.19-5.26 (m, 1 H) 5.10-5.17 (m, 1 H) 4.26 (q, J=6.95 Hz, 2 H) 3.68-3.85 (m, 2 H) 3.52-3.68 (m, 2 H) 1.28 (t, J=7.14 Hz, 3 H) 1.12-1.21 (m, 6 H).
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:9].[Si:20]([O:27][CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][NH:31][CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>>[Si:20]([O:27][CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][N:31]([CH:7]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:2]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:9])[CH2:30]1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: COc1ccc(COC(=O)CC2CCCC2O)cc1
Product: COc1ccc(COC(=O)C(C2CCCC2)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 233 mg (0.88 mol) of (R/S)-2-hydroxy-cyclopentylacetic acid, 4-(methoxy)benzyl ester (from EXAMPLE 15, Step B) and 209 mg (0.71 mmol) of 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenylpyrrolidine (from EXAMPLE 1, Step E) using a procedure analogous to that described in EXAMPLE 1, Step G to provide 326 mg (84%) of the title compounds as a mixture of diastereomers: RF: 0.64 (4:1 v/v hexanes/EtOAc); 1H NMR (300 Hz) δ 0.0 (2 s, 6H), 0.84, 0.85 (2 s, 9H), 1.18 (m, 11H), 1.42-1.82 (m, 7H), 2.23-2.34 (m, 2H), 2.65-3.18 (m, 6H), 3.43-3.59 (m, 2H), 3.81 (s, 3H), 5.01-5.19 (m, 2H), 6.85-6.91 (m, 2H), 7.14-7.36 (m, 7H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([S:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([O:13]CC)=[O:12])[NH:4][N:3]=1.Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.Br.[OH-].[Na+]>C(O)(C)C.O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:1][C:2]1[CH:6]=[C:5]([S:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[C:11]([OH:13])=[O:12])[NH:4][N:3]=1
Reactant: Clc1ccccn1
Reactant: CCOC(=O)c1cccc(Sc2cc(N)n[nH]2)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1cccc(Sc2cc(Nc3ccccn3)n[nH]2)c1
Temperature: 175 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
A stirred solution of ethyl 3-(3-amino-1H-pyrazol-5-ylthio)benzoate (0.150 g, 0.57 mmol), 2-chloropyridine (0.130 g, 1.14 mmol) in isopropanol (2 mL) was treated with hydrobromic acid (0.150 mL) and heated at 175° C. in a microwave oven for 30 minutes. The mixture was then diluted with water (1.5 mL) and treated with sodium hydroxide (1 pellet). The reaction was stirred at room temperature overnight, then concentrated to dryness. The residue was dissolved in methanol, acidified with conc. hydrochloric acid and purified on Prep HPLC (MeCN/H2O/5 mM NH4OAc) to give the title material (0.113 g, 62%) as a solid. The compound was used as such in the next reaction.
Reaction SMILES: C(C1C=CC([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-])=O)=[CH:15][CH:16]=3)[C:11](=[O:22])[N:10]2CCCNC(=O)OC(C)(C)C)=CC=1)#N.[N+](C1C=C2C(CCNC2=O)=CC=1)([O-])=O.[H][H]>[Pd].CO>[NH2:19][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH2:9][NH:10][C:11]2=[O:22])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc([N+](=O)[O-])ccc2CC1c1ccc(C#N)cc1
Agent: [Pd]
Agent: O=C1NCCc2ccc([N+](=O)[O-])cc21
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NCC2

Procedure:
Compounds within the scope of the invention may be prepared as depicted in Scheme 1. In general, an aldehyde, such as 4-cyanobenzaldehyde, and an amine, such as N1-boc-1,3-diamino-n-propane can be reacted in a suitable solvent (eg., THF or chloroform) to form an imine intermediate. The solvent may then be evaporated under reduced pressure, and the residue redissolved in DMF. The imine is then reacted with 7-nitro-homopthallic anhydride, (i.e., 7-Nitro-1H-2-benzopyran-1,3(4H)-dione) to produce a 7-nitro-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(3-(4-cyanophenyl)-7-nitro-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 1). The nitro group of the 7-nitro-3,4-dihydroisoquinolin-1(2H)-one can then be treated with a reducing agent, such as hydrogen in the presence of 10% palladium on carbon, in a suitable solvent (MeOH) to give a 7-amino-3,4-dihydroisoquinolin-1(2H)-one, such as tert-butyl (3-(7-amino-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)propyl)carbamate (Intermediate 13). The 7-amino-3,4-dihydroisoquinolin-1(2H)-one may be dissolved in a suitable solvent (eg., benzene) and then be treated with an organic isocyanates, such as 4-acetylphenyl isocyanates, in the presence of a strong base (eg, DIPEA) to produce a urea, such as tert-butyl {3-[7-({[(4-acetylphenyl)amino]carbonyl}amino)-3-(4-cyanophenyl)-1-oxo-3,4-dihydroisoquinolin-2(1H)-yl]propyl}carbamate (Intermediate 23), a compound which falls under the scope of the invention. At this stage, those skilled in the art will appreciate that many additional compounds that fall under the scope of the invention may be prepared by performing various common chemical reactions. For instance, a sulfide group may be oxidized to sulfoxide or sulfone groups by treatment with a suitable oxidizing agent (eg., m-chloroperbenzoic acid). Or, for example, the t-butylcarbamate group may be removed by treatment with a strong acid, such as trifluoroacetic acid, to give an amine product, such as 1-(4-acetyl phenyl)-3-[2-(2-aminoethyl)-3-(4-cyanophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl]urea (Compound 2). Details of certain specific chemical transformations are provided in the examples.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH2:9]1)C1C=CC=CC=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[C:33](Cl)=[O:34]>>[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([C:33]([N:8]2[CH2:13][CH2:12][C@H:11]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C@H:10]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH3:21])[CH2:9]2)=[O:34])[CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CCC1=O
Reactant: C1COCCN1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1ccccc1[C@@H]1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1N1CCOCC1

Procedure:
The title compound, MS: m/e=501.2 (M+H+), was prepared in accordance with the general method of example 26 from 1-benzyl-3-o-tolyl-piperidin-4-one, morpholine and 3,5-bistrifluoromethyl-benzoyl chloride.
Reaction SMILES: BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(C(C)(C)C)=CC=3)(=O)=O)C=2C=1.[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:51])[F:50])[CH:47]=[CH:48][C:42]=3[CH2:41][NH:40][C:39]=2[CH:53]=1.BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CNC=2C=1.[F:74][C:75]([F:88])([F:87])[O:76][C:77]1[CH:82]=[CH:81][C:80]([S:83](Cl)(=[O:85])=[O:84])=[CH:79][CH:78]=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C>>[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:42]=3[CH2:41][N:40]([S:83]([C:80]3[CH:79]=[CH:78][C:77]([O:76][C:75]([F:74])([F:87])[F:88])=[CH:82][CH:81]=3)(=[O:85])=[O:84])[C:39]=2[CH:53]=1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(I)cc1NC2
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Product: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21

Procedure:
The title compound was prepared following the procedure described for intermediate 53 substituting 8-iodo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 37) for 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine, and 4-(trifluoromethoxy)benzenesulfonyl chloride substituted for [(4-tert-butylphenyl)-sulfonyl chloride. LC/MS: m/e 615.8 (M+H)+. 1H NMR (500 MHz, acetone-d6): δ 7.80 (1H, d, J=2.0 Hz), 7.79 (1H, d, J=7.8 Hz), 7.66 (1H, dd, J=8.5, 2.0 Hz), 7.55 (2H, d, J=8.4 Hz), 7.29 (2H, d, J=8.2 Hz), 7.17 (1H, d, J=7.6 Hz), 7.15 (2H, d, J=8.6 Hz), 4.70-4.90 (2H, br).
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][N:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][Cl:9].[CH3:12][N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][C:16](=[O:24])[C:15]2=[CH:25][S:26][CH:27]=[C:14]12.Cl>CCOCC.CN(C)C=O>[ClH:9].[CH3:4][N:5]([CH3:11])[CH2:6][CH:7]([CH3:10])[CH2:8][N:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:13]([CH3:12])[C:14]2=[CH:27][S:26][CH:25]=[C:15]2[C:16]1=[O:24]
Reactant: CC(CCl)CN(C)C
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(CN(C)C)CN1C(=O)c2cscc2N(C)c2ccccc21
Reaction time: 18 h

Procedure:
A mixture of 0.47 g. of 55% sodium hydride-mineral oil dispersion and 0.91 g. of 3-dimethylamino-2-methylpropylchloride hydrochloride in 35 ml. of dry dimethylformamide is stirred at room temperature for 0.5 hours. To the mixture is added 0.6 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and stirring is continued for 18 hours. The reaction mixture is cooled, quenched with water and extracted with chloroform. The dried chloroform extracts are concentrated to an oil, which is chromatographed on silica gel preparative thin layer chromatographic (tlc) plates with 10:1 benzene:methanol to give an oil. An ethanolic solution of the oil is treated with anhydrous hydrogen chloride and diluted with ether to give a white solid, m.p. 231°-233°C. (dec.).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]=5[C:29]([NH2:31])=[O:30])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25][C:24]=5[C:29]([NH2:31])=[O:30])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CNCC3)cc1OCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3=C(C(N)=O)CN(C)CC3)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 4-[2-(2-isopropyl-2H[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1,2,5,6-tetrahydro-pyridine-3-carboxylic acid amide (0.15 g, 0.35 mmol) in DCM (16 mL) and methanol (8 mL) was added formaldehyde (0.053 mL, 37% aq., 0.7 mmol), sodium triacetoxyborohydride (0.11 g, 0.52 mmol) and acetic acid (24 μL, 0.42 mmol). The reaction mixture was stirred at RT for 16 h. Sodium hydrogen carbonate (aq.) and 10% Methanol in DCM were added to the mixture and the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 414 (94 mg, 62%). LCMS: RT=2.31 min, [M+H]+=434. 1H NMR 400 MHz (DMSO-d6) δ: 8.32 (1H, d, J=8.35 Hz), 7.92 (1H, s), 7.91 (1H, d, J=0.62 Hz), 7.11 (1H, br, s), 7.08 (1H, dd, J=8.37, 1.83 Hz), 7.02 (1H, br, s), 6.98 (1H, d, J=1.79 Hz), 5.94-5.86 (1H, m), 4.53-4.46 (4H, m), 3.15 (2H, s), 2.61 (2H, s), 2.46 (2H, s), 2.35 (3H, s), 1.48 (6H, d, J=6.60 Hz)
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH2:6][CH2:7]Cl)=[O:4].C(OC)(=O)[CH2:12][OH:13].C(C1C=CC=CC=1)(C)(C)C.C([O:29]CC)C>>[OH:1][C:2]([CH3:10])([CH3:9])[C:3]([O:5][CH2:6][C:7]([O:13][CH3:12])=[O:29])=[O:4]
Reactant: CC(C)(O)C(=O)OCCCl
Reactant: CCOCC
Reactant: COC(=O)CO
Solvent: CC(C)(C)c1ccccc1
Product: COC(=O)COC(=O)C(C)(C)O

Procedure:
A 6 mL aliquot of an ethyl ether solution containing 0.25M 2-chloroethyl 2-hydroxy-2-methylpropionate, 0.25M methyl glycolate, and 0.125% tert-butylbenzene was added to 0.5 g Lipase P30. After mixing for 48 hr at room temperature, the conversion of 2-chloroethyl 2-hydroxy-2-methylpropionate to the title compound was estimated (by GC, Method A) to be 47%. The GC peak assigned to the title compound was confirmed by HRMS: calcd for C6H10O5Tms (M-CH3) 233.0845, obsd 233.0870. In identical reactions substituting Lipase AK, Lipase MAP10, Lipase G, Lipase AP12, Protease M, or porcine pancreatic lipase for Lipase P30, the relative values for conversions at 48 hr (Lipase P30=100) were 33, 32, 16, 14, 13 and 2, respectively.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[H][H].[C:15]1(=[O:20])[O:19][CH2:18][CH2:17][CH2:16]1>CN(C)C=O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:18][CH2:17][CH2:16][C:15]([OH:20])=[O:19])[CH:3]=1
Reactant: O=C1CCCO1
Reactant: Cc1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(CCCC(=O)O)c2ccccc12

Procedure:
3-Methylindole (13.1 g; 1 eq) and sodium hydride (5 g of 50% suspension--1 eq) were melted together in a 3-neck round bottom flask immersed in 100° C. oil bath until evolution of hydrogen gas ceased. The mixture was cooled down and dissolved in 250 mL of dry dimethylformamide. Butyrolactone (17.2 g--2 eq) was added and the solution was refluxed for 7 hr and poured on ice. The mixture was extracted with diethyl ether, and the acid was liberated with 10% hydrochloric acid solution. The mixture was extracted with diethyl ether. Evaporation of the extract gave a residue which was chromatographed on silica gel using 10% (v/v) ethyl acetate in benzene. Evaporation of the appropriate eluates gave 5.5 g of the title compound, mp 82°-84° C.