Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:9]2[NH:8][C:7]3[C:13]4[C:18]([CH2:19][C:6]=3[C:5]=2[C:4]=1[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=4.O1CCN(B)CC1.Cl.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][C:9]2[NH:8][C@@H:7]3[C:13]4[C:18]([CH2:19][C@@H:6]3[C:5]=2[C:4]=1[CH3:20])=[CH:17][CH:16]=[CH:15][CH:14]=4
Reactant: COc1c(C)cc2[nH]c3c(c2c1C)Cc1ccccc1-3
Agent: BN1CCOCC1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(C)cc2c(c1C)[C@H]1Cc3ccccc3[C@H]1N2
Yield: 917 %

Procedure:
To an solution of 0.8 g (0.3 mmol) of 5,10-dihydro-8-methoxy-7,9-dimethylindeno[1,2-b]indole and 1,21 g of morpholino borane in 4 ml of dioxane was added dropwise 1 ml of conc. hydrochloric acid. The mixture was refluxed for 30 minutes, then cooled whereupon 3 ml of 6M hydrochloric acid was added. The resulting mixture was then refluxed for 15 minutes. After cooling the solution was alkalinized with aqueous sodium hydroxide and extracted three times with ether. Drying (MgSO4) and evaporation gave a crude product, which was crystallized by dissolving in ethyl acetate and addition of light petroleum at -20° C. Filtration gave 0.73 g (92%) of the title compound. 1H NMR(CDCl3) 2.08 (3H,s), 3.15-3.25 (1H,dd), 3,42-3,55 (1H,dd), 3.7 (3H,s), 4.1-4.22 (1H,t) 5.22-5.28 (1H,d), 6.42-6.46 (1H,d), 6.6- 6.65 (1H,d) 7.14-7.25 (3H,m), 7.3-7.4 (1H,m).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH:28]=[CH:27]1>C(O)C.[OH-].[Na+]>[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:26](=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])([OH:25])=[O:24]
Reactant: NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=C1C=CC(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C\C(=O)NCCCCCCCCCCCCCCCCCCCCCC(=O)O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 105.9 %

Procedure:
In a mixture of 100 ml of ethanol and 50 ml of 1N aqueous sodium hydroxide solution, 22-aminodocosanoic acid (400 mg, 1.12 mmoles) was dissolved at 40° C. To the obtained solution, the temperature being maintained at 40° C., maleic anhydride (4.39 g, 44.8 mmoles) was gradually added over a period of 5 hours. The reaction mixture was kept at a pH of 8-10 during the addition, and the mixture was stirred for additional 30 minutes and then treated in the same manner as in Reference Example 4, to give N-(21-caboxyheneicosyl)maleamic acid (538 mg, 83%) having the following properties.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.Cl.[CH2:27]([O:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH3:28].C(N(C(C)C)CC)(C)C>ClCCl>[C:7]([O:9][CH2:10][C:11](=[O:13])[N:32]([CH2:33][CH2:34][O:35][CH2:36][CH3:37])[CH2:31][CH2:30][O:29][CH2:27][CH3:28])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CCOCCNCCOCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCN(CCOCC)C(=O)COC(=O)/C=C/C(=O)OC
Yield: 14.7 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.80 g, 6.14 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (1.40 g, 7.37 mmol) in 20 mL of dichloromethane (DCM) at ca. 0° C. bis(2-Ethoxyethyl)amine hydrochloride (1.18 g, 7.37 mmol) (1.18 g, 7.37 mmol) and diisopropylethylamine (DIEA) (1.34 mL, 0.99 g, 7.67 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes (1:1) afforded 0.30 g (15% yield) of the title compound (27) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 6.97 (d, J=15.6 Hz, 1H), 6.94 (d, J=1.6 Hz, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.56-3.43 (m, 12H), 1.19 (q, J=7.6 Hz, 6H). MS (ESI): m/z 332.20 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1.[NH2:20][OH:21].Cl.C([O-])([O-])=O.[K+].[K+].O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18](=[N:20][OH:21])[NH2:19])=[CH:4][CH:3]=1
Reactant: N#CCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(Cc1c(-c2ccc(Cl)cc2)nc2ccccn12)=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)acetonitrile (0.13 mol, 34.0 g) in absolute EtOH (300 mL) was added NH2OH.HCl (0.32 mol, 22.1 g) and K2CO3 (0.32 mol, 44.1 g), respectively. The mixture was stirred at r.t. overnight, filtrated, and washed with EtOH for 3 times. The EtOH-filtrate was concertrated to small volume, and the precipitation was collected by filtration, to give one partial products. The solid was dispersed into water, sonicated for 10 mins, filtrated, washed with water, and dried in vacuo, to give another partial products. Combined two portions products added up to 25.0 g (65.4%). m/e+=301 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[C:42]2([CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1>>[O:38]1[C:42]2([CH2:47][CH2:46][N:45]([C:21]3[N:20]=[C:19]([O:18][C:11]4[C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:8]([NH:7][C:5](=[O:6])[C:4]5[CH:29]=[C:30]([N:32]6[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]6)[CH:31]=[C:2]([F:1])[CH:3]=5)=[CH:9][CH:10]=4)[CH:24]=[CH:23][N:22]=3)[CH2:44][CH2:43]2)[O:41][CH2:40][CH2:39]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: O=C(Nc1ccc(Oc2ccnc(N3CCC4(CC3)OCCO4)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 1,4-dioxa-8-aza-spiro[4.5]decane according to conditions described in general procedure C. Mp: 195-196° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.46-1.59 (s, 10 H), 3.27-3.31 (m, 4 H), 3.56 (s, 4 H), 3.84 (s, 4 H), 6.20-6.22 (m, 1 H), 6.95 (d, J=12.8, 1 H), 7.15 (d, J=9.1 Hz, 1 H), 7.40-7.42 (m, 1 H), 7.45 (s, 1 H), 7.55-7.60 (m, 3 H), 7.83 (d, J=7.7 Hz, 1 H), 7.97 (d, J=8.0 Hz, 1H), 8.25-8.27 (m, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [C:1](O)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([OH:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22]
Reactant: C=CCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCCCCCCCCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of 5.08 g of 21-docosenoic acid in 50 mL of tetrahydrofuran was added dropwise with stirring to a slurry of 0.90 g of lithium aluminum hydride in 100 mL of tetrahydrofuran at 0° C., and the reaction mixture was stirred overnight at room temperature. Excess lithium aluminum hydride was quenched by the addition of 5 mL of ethyl acetate followed by 30 mL of 2 N aqueous sodium hydroxide. Lithium salts separated as a white, viscous mass, and the supernatant liquid was transferred to a separatory funnel. The precipitated salts were extracted with two 50 mL portions of diethyl ether, and the combined organic solutions were washed with 100 mL of water. The cloudy aqueous phase was acidified with 1 N aqueous hydrochloric acid and extracted with two 50 mL portions of diethyl ether. The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration provided 4.40 g of 21-docosen-1-ol as a white solid, m.p. 62-64° C., which was used without further purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=1>CN(C=O)C.CCOCC>[Br:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=1
Reactant: Oc1ccccc1
Reactant: Brc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Brc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenol (5.08 g; 54 mmol) in 30 ml dry DMF at 0 C. was added portionwise NaH (1.98 g; 66 mmol; 80% dispersion in oil). The mixture was stirred 30 min at r.t. then 1,3-dibromobenzene (33 ml; 273 mmol) and Cu2O (3.95 g; 28 mmol) were added. The final mixture was heated to reflux for 4 h, cooled to r.t., diluted with Et2O (200 ml), washed with water (3×200 ml), NaOH (1.0 M; 2×100 ml) and brine, dried over MgSO4 and concentrated. Flash chromatography with hexane afforded the desired material.
Reaction SMILES: [C:1]1([C:8]([C:10]([O:12][C:13](=[O:23])[C:14](=[O:22])[C:15]2[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH2:17])=[O:11])=[O:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH2:3].[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34])(=O)=O>O=P(N(C)C)(N(C)C)N(C)C>[CH:33]([O:32][CH2:31][CH2:30][NH:3][C:2]1[C:1]([C:8]([C:10]([O:12][C:13](=[O:23])[C:14](=[O:22])[C:15]2[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:17][CH2:30][CH2:31][O:32][CH:33]([CH3:34])[CH3:35])=[O:11])=[O:9])=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:35])[CH3:34]
Reactant: Nc1ccccc1C(=O)C(=O)OC(=O)C(=O)c1ccccc1N
Reactant: Cc1ccc(S(=O)(=O)OCCOC(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)OCCNc1ccccc1C(=O)C(=O)OC(=O)C(=O)c1ccccc1NCCOC(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material is prepared as follows: 3 g of isatic acid anhydride are dissolved in 50 ml of distilled hexametapol(=hexamethylphosphoric acid triamide). The solution is cooled to 5°, and 0.96 g of 55% NaH (freed of oil with hexane) is added. The mixture is stirred for 30 minutes at RT and then 5.67 g of O-(2-isopropyloxyethyl) tosylate are added. The mixture is stirred for 30 minutes at RT and for one hour at 50°. The mixture is left to stand overnight and is poured onto ice, and the organic layer is separated off and washed with water. The mixture is concentrated by evaporation, and the residue is digested with ether and filtered off with suction, yielding N-(2-isopropyloxyethyl)isatic acid anhydride, m.p. 107°-108°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[CH:17]=3)=[C:11]([CH3:18])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Temperature: 120 °C
Yield: 42.7 %

Procedure:
A mixture of 1-(4-fluoro-phenyl)-5-(1H-imidazol-4-yl)-4-methyl-1H-[1,2,3]triazole (100 mg, 0.411 mmol), 4-fluorobenzotrifluoride (105 μL, 0.822 mmol) and potassium carbonate (114 mg, 0.82 mmol) in DMF (2.0 mL) was stirred under Ar in a sealed flask and heated at 120° C. for 48 h. After cooling to room temperature the mixture was poured into HCl (1 N) and extracted with ethyl acetate and the combined extracts washed with water, brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 100% ethyl acetate in heptane) afforded the title compound (68 mg, 43%) as an off white solid. MS: m/e=388.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)(=[O:10])=[O:9].[NH2:18][C:19]1[C:20]([C:41]#[N:42])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[F:40])=[CH:23][N:24]=1>>[NH2:18][C:19]1[C:20]([C:41]#[N:42])=[N:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([N:11]3[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]3)(=[O:10])=[O:9])=[CH:27][C:26]=2[F:40])=[CH:23][N:24]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: O=C1CN(S(=O)(=O)c2ccccc2Br)CCN1
Product: N#Cc1nc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCNC(=O)C3)cc2F)cnc1N

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-((2-bromophenyl)sulfonyl)piperazin-2-one and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C21H17FN6O3S, 452.11; m/z found, 453.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.65 (d, J=2.1, 1H), 8.05 (dd, J=8.1, 1.3, 1H), 7.85 (m, 1H), 7.65 (m, 1H), 7.55 (m, 1H), 7.36 (dd, J=7.6, 1.3, 1H), 7.26-7.17 (m, 2H), 3.29 (s, 2H), 3.04 (s, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH2:10][CH3:11])[N:5]=1)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(O[C@H:26]1[NH:29][C:28](=[O:30])[C@@H:27]1[C@H:31]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH3:32])(=O)C.[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[CH2:10]([N:6]1[C:7]([CH3:9])=[CH:8][C:4]([C:1]([CH2:2][C@H:26]2[NH:29][C:28](=[O:30])[C@@H:27]2[C@H:31]([O:33][Si:34]([C:37]([CH3:38])([CH3:40])[CH3:39])([CH3:36])[CH3:35])[CH3:32])=[O:3])=[N:5]1)[CH3:11]
Reactant: CCn1nc(C(C)=O)cc1C
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nc(C(=O)C[C@H]2NC(=O)[C@@H]2[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41.9 %

Procedure:
3-Acetyl-1-ethyl-5-methylpyrazole (3.51 g) in dry tetrahydrofuran (THF) (150 ml) under an argon atmosphere was cooled in an acetone/solid carbon dioxide bath and then treated with a 1M solution of lithium bis(trimethylsilyl)amide (50 ml). The mixture was stirred for 45 minutes and then (3R,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidinone (6.6 g) was added as a solid under a blanket of argon. The mixture was stirred in the cold for 3.5 h. Saturated aqueous ammonium chloride was then added, followed by ethyl acetate, and the mixture was allowed to warm to room temperature. A little water was added and the layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extracts were washed with saturated brine, dried and evaporated. Chromatography on silica gel, eluting with ethyl acetate/hexane mixtures gave the title compound (3.65 g), νmax (CH2Cl2) 3411, 1761, 1678, 1376, 1151, and 838 cm-1 ; δ(CDCl3) 0.064 (6H, s), 0.86 (9H, s), 1.20 (3H,d, J 6.3 Hz), 1.44 (3H, t, J 7.3 Hz) 2.31 (3H, s), 2.89 (1H, dd, J 1.8 & 4.9 Hz), 3.15 (1H, dd, J 10.0 & 17.1 Hz), 3.50 (1H, dd, J 3.5 & 17.0 Hz), 4.06-4.25 (4H, m), 6.11 (1H, s), 6.53 (1H, s). (Found m/z 379.2296. C19H33N3O3Si requires m/z 379.2291).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=O)[CH2:31][CH2:30]2)[CH2:27][CH2:26]1.Cl.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]2[CH2:58][C:57]3[CH:56]=[N:55][N:54]([CH3:59])[C:53]=3[NH:52][C:51]3[CH:60]=[CH:61][CH:62]=[CH:63][C:50]2=3)=[O:48])=[C:43]([F:64])[CH:42]=1>CN(C=O)C.CCN(C(C)C)C(C)C>[F:64][C:43]1[CH:42]=[C:41]([CH:46]=[CH:45][C:44]=1[C:47]([N:49]1[CH2:58][C:57]2[CH:56]=[N:55][N:54]([CH3:59])[C:53]=2[NH:52][C:51]2[CH:60]=[CH:61][CH:62]=[CH:63][C:50]1=2)=[O:48])[CH2:40][NH:39][C:35]([CH:32]1[CH2:31][CH2:30][N:29]([CH2:28][CH:25]2[CH2:26][CH2:27]2)[CH2:34][CH2:33]1)=[O:37]
Reactant: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CN)cc1F)C2
Reactant: O=C(O)C1CCN(CC2CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)C3CCN(CC4CC4)CC3)cc1F)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46 %

Procedure:
HBTU (227 mg, 0.6 mmol) was added to a solution of 1-cyclopropylmethyl-piperidine-4-carboxylic acid from Example E15a (99 mg, 0.45 mmol) in DMF (5 ml) and DIEA (to pH9). The mixture was stirred at room temperature for 1 h. (4-Aminomethyl-2-fluoro-phenyl)-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E90.2 (116 mg, 0.3 mmol) was added and the mixture was stirred at room temperature for 18 h. Solvents were removed in vacuo and azeotroped with toluene. The residue was redissolved in EtOAc, washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% 35% ammonia:19% methanol:80% dichloromethane) to give a white solid identified as the title compound (71.5 mg, 46%).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[C:20]([O:19][C:17]1[CH:16]=[CH:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)Oc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)Oc1ccc2c(n1)OCCNC2
Temperature: 40 °C
Reaction time: 48 h
Yield: 27.8 %

Procedure:
A mixture of the compound obtained in step 1 (0.81 g), 20% Pd(OH)2/C (0.081 g) and methanol (10 mL) was stirred at 40° C. for 2 days under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (solvent gradient; 40→100% ethyl acetate/hexane) to give the title compound (0.16 g, 57%) as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH:15]2[CH2:18][N:17]([CH3:19])[CH2:16]2)[C:13]#[N:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[ClH:26]>CC(CC(C)C)=O>[ClH:26].[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH:15]2[CH2:18][N:17]([CH3:19])[CH2:16]2)[C:13]([NH2:14])=[O:2])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: CC(=O)CC(C)C
Product: CN1CC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Temperature: 70 °C

Procedure:
To 60 ml. of concentrated sulfuric acid preheated to 60° C. was added 21.7 g. (0.082 mole) of α,α-diphenyl-α-(1-methyl-3-azetidinyl)acetonitrile at a rate so as to maintain a temperature of 60°-70° C. The solution obtained was heated to 70° C. for 18 hrs. and extracted with chloroform. The chloroform extract was dried over sodium sulfate and concentrated and the residue crystallized from ethyl acetate-isopropyl alcohol to give 13.8 g. of the free base (60%) melting at 171°-174° C. The base was treated with hydrogen chloride in isobutyl methyl ketone and the salt recrystallized from isopropyl alcohol to give 9 g. of product melting at 182°-185° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 500 mL round-bottomed flask was charged with 4-bromobenzenesulfonyl chloride (10.00 g, 39.1 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of benzene and aluminum chloride (6.26 g, 47.0 mmol). After stirring at room temperature for 12 h, the mixture was diluted water (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried (MgSO4) and concentrated to give 1-bromo-4-(phenylsulfonyl)benzene (10.50 g) as a white solid.
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].C(N1CCOCC1)C.ClC(OCC(C)C)=O.[NH2:30][C@H:31]([C:39]([O:41][CH3:42])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C1COCC1.CN(C=O)C.CCOC(C)=O>[NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([NH:30][C@H:31]([C:39]([O:41][CH3:42])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:6])[CH3:3]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: -18 °C
Reaction time: 1 h

Procedure:
To a solution of Boc-Ala-OH (0.50 g, 2.64 mmol) and N-ethyl morpholine (0.336 mL, 2.64 mmol) in THF (10 mL) at −18° C. was added i-butyl chloroformate (0.317 mL, 2.44 mmol). After an activation period of 10 min a solution of Phe-OMe (0.406 g, 1.88 mmol) and N-ethyl morpoholine (0.240 mL, 1.88 mmol) in DMF (4 mL) was added dropwise. The reaction mixture was stirred under nitrogen at −18° C. for 1 h then overnight at room temperature. The reaction mixture was cooled to 0° C. followed by addition of NaHCO3 (10 mL, 5% aqueous solution). After 10 min this solution was warmed to room temperature and diluted with EtOAc (5 mL). The aqueous layer was removed and washed 2 with 20 mL EtOAc. The organics were combined and washed 3 with 10 mL 1 N HCl, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (70% EtOAc/haxanes) to the product as a white solid (0.159 g, 91%). 1H NMR (CDCl3) 7.31 (m, 3H), 7.14 (m, 2H), 6.63 (d, J=7.4 Hz, 1H), 5.05 (br s, 1H), 4.87 (q, J=6.9 Hz, 1H), 4.18 (br s, 1H), 3.73 (s, 3H), 3.18 (dd, J=13.9, 6.1 Hz, 1H), 3.10 (dd, J=13.9, 5.8 Hz, 1H), 1.46 (s, 9H), 1.33 (d, J=6.9 Hz, 3H); 13C NMR (CDCl3) 172.2, 171.7, 155.3, 135.7, 129.2, 128.5, 127.1, 80.0, 53.1, 52.3, 50.0, 37.8, 28.2, 18.2; IR (KBr) 3315, 2978, 1744, 1708, 1666, 1522, 1453, 1366,1168; HRMS calcd for C18H27N2O (M+H)+ 351.1920 found 351.1916.
Reaction SMILES: C([CH:3]([C:20]([OH:22])=[O:21])[N:4]([C:10](OCC1C=CC=CC=1)=O)[CH2:5][P:6]([CH3:9])([CH3:8])=[S:7])C.[CH3:23]COCC>Br.C(O)(=O)C>[CH2:10]([N:4]([CH2:5][P:6]([CH3:9])([CH3:8])=[S:7])[CH2:3][C:20]([OH:22])=[O:21])[CH3:23]
Reactant: CCC(C(=O)O)N(CP(C)(C)=S)C(=O)OCc1ccccc1
Reactant: CCOCC
Agent: Br
Solvent: CC(=O)O
Product: CCN(CC(=O)O)CP(C)(C)=S
Reaction time: 1 h

Procedure:
Ethyl N-carbobenzoxy-N-(dimethylthiophosphinylmethyl)glycine (2 g., 0.005 mole) was dissolved in 36% hydrogen bromide (8 ml) in glacial acetic acid at 0° C. and the resulting mixture was stirred for one hour. Ether was added and the oily precipitate was isolated by decanting the ether layer. The oil was washed with ether twice, then suspended in benzene and treated with propylene oxide. The solution was concentrated in vacuo to yield ethyl N-(dimethylthiophosphinylmethyl)glycine (0.7 g., 0.002 mole) as an amber oil, ND22 =1.4832.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])[CH2:2][CH2:3][CH3:4].[CH3:12][NH:13][C:14](=O)[O:15]CC.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccccc1O
Reactant: CCOC(=O)NC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCCc1ccccc1OC(=O)NC

Procedure:
To a solution of 2-sec butylphenol (1.5 g, 0.01 mole) and ethyl N-methylcarbamate (1.03 g, 0.01 mole) in toluene (10 ml) at 60° C., phosphoryl chloride (0.77 g, 0.05 mole) was added dropwise during 0.5 hours and the contents refluxed for 5 hours. It was worked up as described earlier to furnish 2-sec butylphenyl N-methylcarbamate of the formula (III).