Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][S:14][C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:15]#[N:16])=[CH:5][C:4]=2[NH:3]1.[N-:17]=[N+:18]=[N-:19].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C.O>[NH:17]1[C:15]([C:6]2[CH:7]=[CH:8][C:9]3[C:10]4[S:14][CH:13]=[CH:12][C:11]=4[C:2](=[O:1])[NH:3][C:4]=3[CH:5]=2)=[N:16][N:19]=[N:18]1
Reactant: N#Cc1ccc2c(c1)[nH]c(=O)c1ccsc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(-c3nnn[nH]3)ccc2c2sccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
4-oxo-4,5-dihydrothieno[3,2-c]quinoline-7-carbonitrile (1.0 eq, 20 mg, 0.088 mmol) was dissolved in anhydrous DMF (0.15 ml). Sodium azide (4.0 eq, 23 mg, 0.354 mmol) and ammonium chloride (4.0 eq, 19 mg, 0.354 mmol) were added and the mixture stirred at 120° C. overnight. The reaction mixture was cooled down and water was added. Addition of aqueous 6 N HCl induced formation of a precipitate. After filtration and drying in vacuo, 7-(1H-tetrazol-5-yl)thieno[3,2-c]quinolin-4(5H)-one was isolated as a greenish solid (18 mg, 76% yield)). LCMS (ES): 95% pure, m/z 270 [M+1]+, 242 [M+1-N2]+; 1H NMR (DMSO-d6, 400 MHz) δ 7.64 (d, J=5.2, 1H), 7.86 (dd, J=1.6, J=8.4, 1H), 7.89 (d, J=5.2, 1H), 8.09 (d, J=8.0, 1H), 8.16 (d, J=1.6, 1H), 12.03 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH2:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:9]2[CH2:10][O:22]2)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(c1ccc(Cl)cc1)C(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)C(c1ccc(Cl)cc1)C1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4 g of the product of Example 1 and 4.5 g of m-chloroperbenzoic acid in 50 mL of chloroform was stirred overnight at room temperature and filtered. The filtrate was washed with aqueous NaHSO3, aqueous NaHCO3, brine, dried (Na2SO4), and concentrated. The residue was a mixture of diastereomeric epoxides.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([O:15][CH2:16][C@H:17]1[CH2:22][N:21]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=3)[N:26]=[C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[OH:40])[N:24]=2)[CH2:20][CH2:19][N:18]1[C:41]([O:43][C@@H:44]1[CH2:48][CH2:47][O:46][CH2:45]1)=[O:42])C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[F:5][C:4]([F:7])([F:6])[C:2]([OH:3])=[O:1].[OH:15][CH2:16][C@H:17]1[CH2:22][N:21]([C:23]2[C:32]3[C:27](=[CH:28][C:29]([CH3:33])=[CH:30][CH:31]=3)[N:26]=[C:25]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[OH:40])[N:24]=2)[CH2:20][CH2:19][N:18]1[C:41]([O:43][C@@H:44]1[CH2:48][CH2:47][O:46][CH2:45]1)=[O:42]
Reactant: Cc1ccc2c(N3CCN(C(=O)O[C@@H]4CCOC4)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CCN(C(=O)O[C@@H]4CCOC4)[C@@H](CO)C3)nc(-c3ccccc3O)nc2c1
Temperature: 50 °C

Procedure:
To a solution of (2R)-(R)-tetrahydrofuran-3-yl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate TFA salt (94 mg, 0.17 mmol) in ethanol was added Pd(OH)2 (78 mg), and the reaction was heated at 50° C. under an H2 atmosphere at ambient pressure. The reaction was filtered, and purification using reverse phase HPLC (10-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) gave (2R)-(R)-tetrahydrofuran-3-yl 2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate trifluoroacetate. LC/MS: m/z 465.5 (M+H)+ at 2.23 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5](OC)=[O:6])[C:3]=1[NH2:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][OH:6]
Reactant: COC(=O)c1cccc(Cl)c1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Nc1c(Cl)cccc1CO
Temperature: 25 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
A solution of 28.9 g (155 mmol) of methyl 3-chloroanthranilate in 100 ml of ether was added dropwise to a stirred suspension of 7.67 g (202 mmol) of lithium aluminum hydride in 400 ml of ether. After stirring for five hours at room temperature, the grey mixture was treated sequentially with 7.7 ml of water, 7.7 ml of 15% sodium hydroxide and 23 ml of water. The reaction mixture was filtered, and the filtrate was evaporated at reduced pressure. The oily residue was dissolved in ether, and precipitation of the product was induced by addition of hexane. The product was collected by filtration to yield a tan solid in 67% yield, mp 56°-68° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11]O.[BrH:13]>>[BrH:13].[BrH:13].[NH2:8][CH2:9][CH2:10][CH2:11][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCO
Reactant: Sc1ccccn1
Agent: Br
Product: NCCCSc1ccccn1

Procedure:
A solution of 2-mercaptopyridine (2.2 g.) and 3-aminopropanol (1.14 ml.) in hydrobromic acid (48%, 25 ml.) was heated under reflux for 25 hours. The reaction mixture was evaporated to dryness and the oily residual solid recrystallised twice from ethanol to give 2-(3-aminopropylmercapto)pyridine dihydrobromide (3.2 g.) m.p. 186°-188°.
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O.C(OCC)C>CC(C)=O>[O:1]([CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCC1Oc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCCC1Oc1ccccc1
Reaction time: 4.5 h

Procedure:
2-Phenoxy-cyclohexanol (13.64 g, 0.071 mol) was dissolved in acetone (260 mL), cooled to between 0° C. to 5° C., and Jones Reagent (2 M, 78 mL) was added dropwise. The reaction was stirred for 4.5 hours. The reaction mixture was poured into water (250 mL), and diethyl ether (500 mL) was added. The organic phase was separated from the aqueous phase, then washed with water, dried (over MgSO4), and concentrated to yellow crystals. The crystals were recrystallized from pentane to give 2-phenoxy-cyclohexanone (a compound of general Formula III) (10.22 g, 76%). 1 HNMR (CDCl3): δ7.2 (m, 2H), 7.0 (m, 2H), 6.8 (d, 1H), 4.6 (m, 1H), 2.6 (m, 1H), 2.4 (m, 2H), 2.0-1.8 (m, 5H) ppm.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18](Cl)[C:17]([CH3:22])=[CH:16]2>CN(C=O)C>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:17]([CH3:22])=[CH:16]2
Reactant: Nc1ccccc1
Reactant: Cc1cc2cccc(Br)c2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2cccc(Br)c2nc1Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.03 h
Yield: 28.2 %

Procedure:
NaH (60% w/w in mineral oil; 390 mg, 9.75 mmol) was added to a solution of aniline (0.888 mL, 9.75 mmol) in DMF (4.0 mL) at 0° C. and the resulting suspension was stirred at 0° C. for 2 min, then warmed to 25° C. and stirred for 5 min. 8-Bromo-2-chloro-3-methylquinoline (Example 104b; 529 mg, 2.062 mmol) was added as a solid, and the resulting solution was stirred at 25° C. for 1.5 h, then at 80° C. bath for 2.5 h. The mixture was cooled to 25° C. and partitioned between EtOAc (100 mL) and saturated aq. NH4Cl (80 mL). The organic layer was separated and the aq. layer was extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-40% EtOAc/hexanes) furnished 8-bromo-3-methyl-N-phenylquinolin-2-amine (182.0 mg, 0.581 mmol, 28% yield) as a brown oil: m/z (ESI, +ve) 313.1 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:17][O:18][C:19](=[O:51])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][C:36]([S:39]([N:42]3[CH2:47][CH2:46][CH:45]([CH:48]=O)[CH2:44][CH2:43]3)(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[O:31])=[C:24]([F:50])[CH:23]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[F:50][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][C:25]=1[CH2:28][NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([N:42]2[CH2:43][CH2:44][CH:45]([CH2:48][NH:1][CH2:2][C@H:3]([OH:4])[C:5]3[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=3)[CH2:46][CH2:47]2)(=[O:40])=[O:41])=[CH:35][CH:34]=1)=[O:31])[O:21][CH2:20][C:19]([O:18][CH3:17])=[O:51]
Reactant: COC(=O)COc1ccc(CNC(=O)Nc2ccc(S(=O)(=O)N3CCC(C=O)CC3)cc2)c(F)c1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)COc1ccc(CNC(=O)Nc2ccc(S(=O)(=O)N3CCC(CNC[C@H](O)c4ccc(O)c(NS(C)(=O)=O)c4)CC3)cc2)c(F)c1
Yield: 56.9 %

Procedure:
The title compound was prepared from N-[5-(2-amino-1-{R}-hydroxyethyl)-2-hydroxyphenyl]-methanesulfonamide (0.128 g, 0.52 mmol), (4-{3-[4-(4-formyl-piperidine-1-sulfonyl)-phenyl]-ureidomethyl}-3-fluoro-phenoxy)-acetic acid methyl ester (0.5 mmol), glacial acetic acid (0.03 mL, 0.5 mmol) and sodium cyanoborohydride (0.031 g, 0.5 mmol) according to the general procedure used for example 84 (Step E) to give the final product (0.21 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[C:11](=[O:18])[C:10]([C:19]([NH:21][CH2:22][CH2:23][S:24][CH3:25])=[O:20])=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]2[CH2:35][C@H:34]2[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.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>[CH3:25][S:24][CH2:23][CH2:22][NH:21][C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[N:16][CH:15]=[CH:14][CH:13]=2)[N:8]([C:4]2[CH:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]4[CH2:35][CH:34]4[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:29][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[CH:9]=1)=[O:20]
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: CSCCNC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
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: [Na+]
Solvent: CCCO
Product: CCOC(=O)C1CC1c1ccc(-c2cccc(-n3cc(C(=O)NCCSC)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of amide from step 1 (1 eq), ethyl 2-(trans)-(4-bromophenyl)cyclopropanecarboxylate from EXAMPLE 1, step 1 (1 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.05 eq) in n-propanol (0.1M) was stirred at 80° C. for 3 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated in ether/MeOH, isolated by filtration and washed with ether to afford the title compound as a solid.
Reaction SMILES: [OH-].[Na+].[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34]C)=[O:33])=[CH:30][CH:29]=3)[C:20]=1[S:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:10]2>CO>[CH:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH:4]1[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([C:28]3[CH:37]=[CH:36][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=3)[C:20]=1[S:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:15])[CH2:10]2
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2SC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
2M aqueous sodium hydroxide (1.671 mL, 3.34 mmol) was added in one portion to methyl 4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoate (Intermediate #84) (330 mg, 0.67 mmol) in methanol (10 mL). The resulting mixture was stirred at 20° C. for 18 hours. The reaction mixture was concentrated and diluted with water (50 mL), and washed with ether (20 mL). The aqueous solution was adjusted to pH 3 with 2M HCl and extracted with EtOAc (2×25 mL), and the combined extracts washed to sequentially with water (2×20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford 4-[4-(2-adamantylcarbamoyl)-5-cyclohexylsulfanyl-pyrazol-1-yl]benzoic acid (321 mg, 100%).
Reaction SMILES: [Cl:1]/[CH:2]=[C:3](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN>CO>[C:16]1(/[C:3](=[CH:2]/[Cl:1])/[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C\Cl)c1ccccc1
Agent: NN
Solvent: O
Solvent: CO
Product: NC/C(=C\Cl)c1ccccc1
Yield: 56 %

Procedure:
(Z)-1-Chloro-2-phenyl-3-phthalimidopropene (450 mg) is treated as described in Example 14 with hydrazine hydrate (85 mg) in methanol (6 ml). Hydrolysis with 50% aqueous hydrochloric acid (4 ml) and recrystallization of the product from ethanol/diethyl ether gives (Z)-2-phenyl-3-chloroallyl amine as the hydrochloride (142 mg): colorless needles; m.p. 156°-157°;
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9](=[O:24])[CH2:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.Cl>O1CCOCC1>[C:18]1([CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][C:9]([C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:8][CH:7]=2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1ccc(C(=O)CC(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(c1ccccc1)c1ccccc1)c1ccc(=O)[nH]c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
To a solution of 1-(6-methoxy-pyridin-3-yl)-3,3-diphenyl-propan-1-one (468 mg) in 1,4-dioxane (25 ml) was added concentrated aqueous HCl (2.69 ml). The mixture was stirred for 2 h at 100° C. After cooling to room temperature, the mixture was poured into ice and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, dichloromethane/methanol 1:0 to 4:1) to give the title compound (127 mg) as a colorless solid, MS (ESI−): m/z=302.0 [M−H]−.
Reaction SMILES: Cl.CS([S:7][CH2:8][CH2:9][NH2:10])=C(O)O.[C:11]([NH:14][CH2:15][CH2:16][SH:17])(=[O:13])[CH3:12].C(N(CC)CC)C>CO>[NH2:10][CH2:9][CH2:8][S:7][S:17][CH2:16][CH2:15][NH:14][C:11](=[O:13])[CH3:12]
Reactant: CS(SCCN)=C(O)O
Reactant: CC(=O)NCCS
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCSSCCN

Procedure:
The method of S. J. Brois et al. (loc. cit.) was emloyed. Methyl-2-aminoethylsulfenylthiocarbonate hydrochloride in methanol solution was treated with acetylcysteamine at 0° C. The reaction, without triethylamine accelerator, was practically instantaneous.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]2[C:12](CCCCCCCCCCCCCCCCC)=[N:11][N:10]=[C:9]2[CH2:30][OH:31])=[C:5]([C:32](=O)C2C=CC(C)=CC=2)[CH:4]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH3:32][C:5]1[CH:6]=[CH:2][C:1]([C:3]2[S:7][C:6]3[N:8]4[CH:12]=[N:11][N:10]=[C:9]4[CH2:30][O:31][CH2:32][C:5]=3[CH:4]=2)=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCc1nnc(CO)n1-c1sc(CC)cc1C(=O)c1ccc(C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2cc3c(s2)-n2cnnc2COC3)cc1

Procedure:
5-Ethyl-3-(4-methylbenzoyl)-2-(5-heptadecyl-3-hydroxymethyl-1,2,4-triazol-4-yl)thiophene (3 g) obtained in Example 22 was dissolved in ethanol (30 ml). Thereto was added sodium borohydride (0.1 g) with stirring and the mixture was stirred at room temperature for 1 hour. After the ethanol was distilled away, 5% aqueous sodium hydrogencarbonate was added thereto and the liberated oily substance was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and toluene (120 ml) was added to the residue. The mixture was refluxed under heating with stirring and sulfuric acid was gradually added dropwise until the reaction ended. After cooling, 5% aqueous sodium hydrogencarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography. The oily substance obtained was crystallized from hexane to give 0.9 g of 2-ethyl-9-heptadecyl-4-(4-methylphenyl-4H,6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,4]oxazepine as white crystals, melting point 83°-84° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)=[CH:13]3)[CH2:4][CH2:3]1.CCN(CC)CC.[CH2:37]([N:40]=[C:41]=[O:42])[CH2:38][CH3:39]>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([O:8][CH:9]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[CH2:16][CH2:15][N:14]3[C:10]2=[N:11][C:12]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:41]([NH:40][CH2:37][CH2:38][CH3:39])=[O:42])=[CH:27][CH:28]=2)=[CH:13]3)[CH2:6][CH2:7]1
Reactant: CCCN=C=O
Reactant: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccc(N)cc4)nc32)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCNC(=O)Nc1ccc(-c2cn3c(n2)C(OC2CCN(C)CC2)c2ccccc2CC3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 16) (100 mg, 0.258 mmole) in CH2Cl2 (2 mL) is added NEt3 (72 μL, 0.515 mmole) and propylisocyanate (36 μL, 0.387 mmole). The reaction mixture is stirred at room temperature for 24 hours. Solvent is removed under reduced pressure. AcOEt is added to the residue and the organic phase is washed with water and dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (100:0) to (90:10) to afford 1-{4-[4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-3-propyl-urea melting at 130° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[C:23]([F:30])[CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[C:23]([F:30])[CH:22]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4F)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, white solid (69 mg, 75%), MS (ISP) m/z=384.5 [(M+H)+], mp 259° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-chloro-2-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[C:11]([O:19][CH3:20])[CH:10]=1.C(Cl)(=O)C(C)(C)C.[CH:28]([C@H:31]1[CH2:35][O:34][C:33](=[O:36])[NH:32]1)([CH3:30])[CH3:29].[Li]CCCC.O1CCNC1=O.[NH4+].[Cl-]>C1COCC1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:32]2[C@@H:31]([CH:28]([CH3:30])[CH3:29])[CH2:35][O:34][C:33]2=[O:36])=[O:18])=[C:11]([O:19][CH3:20])[CH:10]=1
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: COc1cc(Br)ccc1CC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: O=C1NCCO1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(Br)ccc1CC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
Triethylamine (0.66 mL, 4.75 mmol) was added to a solution of (4-bromo-2-methoxy-phenyl)-acetic acid (1.02 g, 4.162 mmol) in THF (11 mL) in a first round bottom flask under argon atmosphere. The mixture was cooled at −78° C. and pivaloyl chloride (0.513 mL, 4.162 mmol) was added. After stirring for 10 minutes at −78° C., the reaction mixture was warmed to 0° C. and stirred for 30 minutes, then cooled again at −78° C. In second round bottom flask (S)-4-isopropyl-2-oxazolidinone (591.2 mg, 4.577 mmol) was dissolved in THF (20 mL) and cooled to −78° C., and n-BuLi (2.5 M in hexane, 2.0 mL, 4.99 mmol) was added. After stirring for 10 minutes at −78° C., the metallated oxazolidinone mixture in the second flask was added to the mixed anhydride in the first flask at −78° C. The reaction mixture was stirred for 4 hours at 0° C., then at room temperature for 18 hours. A saturated solution of NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified via flash chromatography (hexane/EtOAc, 84/16) to give 1.13 g (77% yield) of (S)-3-[2-(4-bromo-2-methoxy-phenyl)-acetyl]-4-isopropyl-oxazolidin-2-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[NH:14][C:13](=O)[C:12]=2[CH2:11][CH2:10]1)[CH3:2]>P(Cl)(Cl)(Cl)=O>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:25])([F:24])[F:26])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH2:11][CH2:10]1)[CH3:2]
Reactant: CCc1ccccc1N1CCc2c1c1cccc(OC(F)(F)F)c1[nH]c2=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1ccccc1N1CCc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 228.8 %

Procedure:
1-(2-Ethylphenyl)-4-oxo-6-trifluoromethoxy-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(2.5 g, 6.7 mmol) was dissolved in phosphoryl chloride(10 ml), then the reaction mixture was refluxed for 2 hours. After removing the excess phosphoryl chloride by simple distillation, the residue was poured into iced water, neutralized with aqueous solution of sodium hydroxide(1N), stirred at room temperature for 30 minutes, and extracted with dichloromethane(20 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 3.2 g of desired compound as solid in 85% of yield.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].[Br:5][C:6]1[CH:7]=[C:8]([SH:12])[CH:9]=[CH:10][CH:11]=1>>[C:2]([S:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Br:5])[CH:7]=1)([CH3:3])([CH3:1])[CH3:4]
Reactant: C=C(C)C
Reactant: Sc1cccc(Br)c1
Product: CC(C)(C)Sc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Isobutylene was bubbled through 75% H2SO4 solution at-5 degrees C. until 2.65 g (47.2 mmol) of isobutylene had been absorbed. The mixture was treated with 3.8 g (20.1 mmol) of 3-bromothiophenol and then allowed to warm to room temperature and stirred for 72 hours. The reaction mixture was then poured into 40 ml of an ice/water mixture and then extracted with ether. The ether extracts were combined and washed successively with 5% NaOH, water and saturated NaCl solution and then dried (MGSO4) The solvent was removed in-vacuo and the residue distilled (69-75 degrees C., 0.6 mm) to give the title compound as a pale yellow oil. PMR (CDCl3) & 1.30 (9H, s), 7.23 (1H, t, J~8.0 Hz), 7.45-7.54 (2H, m), 7.72 (1H, t, J~1.8 Hz). 4-Bromophenyl 3-methyl-2-butenyl sulfide (Compound 46)