Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([OH:35])=O)[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37].CCN(C(C)C)C(C)C.CN>C1COCC1>[CH3:25][O:26][C:27]1[N:32]=[C:31]([C:33]([NH:2][CH3:1])=[O:35])[CH:30]=[CH:29][C:28]=1[N+:36]([O-:38])=[O:37]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1nc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
HATU (0.606 g, 1.594 mmol) was added to a solution of 6-methoxy-5-nitropicolinic acid (Preparation 190, 0.243 g, 1.226 mmol), DIPEA (0.320 mL, 1.840 mmol) and 2M methylamine solution in THF (1.2 mL, 2.453 mmol) in THF (3.3 mL). The reaction mixture was stirred at room temperature for 3 hours. Further methylamine (0.6 mL) was added and the mixture was stirred for 18 hours. The reaction was quenched with water and concentrated in vacuo. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed twice with water, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with DCM/EtOAc 99/1 to 90/10 to afford the title compound as a yellow solid (182 mg, 70%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>CN(C)C=O>[CH:36]1([CH2:39][N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:26][CH2:25][CH:24]([N:27]5[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:23][CH2:22]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:4][CH2:3][C:2]([F:1])([F:33])[CH2:7][CH2:6]2)=[O:9])[CH2:38][CH2:37]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCC(N2CCOCC2)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC1CC1)N1CCC(N2CCOCC2)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-(4-morpholin-4-yl-piperidin-1-yl)-methanone (example 170), sodium hydride and cyclopropylmethyl bromide in N,N-dimethylformamide, to give the desired product as a white solid (16%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].O>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:28][C:29](=[O:31])[CH3:30])[CH:4]=1
Reactant: CC(=O)CCl
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)=O
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (5.0 g, 16 mmoles) and potassium carbonate (10.62 g, 77 mmoles) in DMF (25 ml) was added chloroacetone (2.32 g of 90% , 22 mmoles) and the mixture stirred vigorously for 5 hours, followed by pouring into water (130 ml) and filtration to give, after drying, 4.57 g of crude product. This was dissolved in methylene chloride and filtered over a short alumina column, followed by concentration and recrystallization of the residue from toluene to give 4.16 g (78%) of the title compound as white solid, mp 105°-106.5°. The NMR (90 MHz) in CDCl3 gave the following resonances: δ 8.44 (s, 1H); 6.16 (s, 1H); 4.72 (s, 2H); 4.4 (s, 2H); 3.6 (m, 2H); 2.68 (m, 6H); 2.28 (s, 3H); 1.08 (t, 6H).
Reaction SMILES: [C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:17](=[O:18])[C:16]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]3[C:14]2=[O:23])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])([OH:3])=[O:2].[N+](=[CH2:37])=[N-]>C(OCC)C>[CH3:37][O:2][C:1]([CH:4]([N:8]1[CH:11]([S:12][N:13]2[C:14](=[O:23])[C:15]3=[CH:22][CH:21]=[CH:20][CH:19]=[C:16]3[C:17]2=[O:18])[CH:10]([NH:24][C:25](=[O:33])[CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:9]1=[O:34])[C:5]([CH3:7])=[CH2:6])=[O:3]
Reactant: C=C(C)C(C(=O)O)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)c2ccccc2C1=O
Yield: 62 %

Procedure:
14 g (purity 70%; 20 mmoles) of 1-(1-carboxy-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one was treated with a diazomethane solution in diethyl ether. After evaporation of the reaction mixture to dryness, benzene was added. After filtering off the phthalimide, the filtrate was concentrated and chromatographed [silica gel; toluene - ethyl acetate 4:1(v/v] to obtain 6.24 g (62% yield) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-phthalimidothio-azetidin-2-one.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[CH:18][CH:19]([C:21]([O:23]C)=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[O:36][CH3:37])=[O:3].[OH-].[Li+]>C(OCC)(=O)C.CO.C(O)(=O)C>[NH2:1][C:2]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:26]=[CH:25][C:16]3[CH2:17][CH2:18][CH:19]([C:21]([OH:23])=[O:22])[O:20][C:15]=3[C:14]=2[CH2:27][CH2:28][CH3:29])=[C:6]([CH2:32][CH:33]2[CH2:35][CH2:34]2)[C:5]=1[O:36][CH3:37])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)OC)C=C2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(C(=O)O)CC2

Procedure:
The compound of Example 68 is saponified with lithium hydroxide using the conditions described in Example 26. Chromatography of the crude residue on silica gel using ethyl acetate/methanol/acetic acid as eluant (90:9.5:0.5) gives the product.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([SH:19])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26]([O:30][C:31](=[O:39])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)([CH3:29])([CH3:28])[CH3:27]>CC(C)=O>[C:26]([O:30][C:31](=[O:39])[CH2:32][O:33][CH2:34][CH2:35][CH2:36][CH2:37][S:19][C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:11]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)COCCCCBr
Reactant: Sc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COCCCCSc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Yield: 82.2 %

Procedure:
To a solution of 500 mg of 5,6-diphenyl-2-pyrazinethiol in 20 ml of acetone, 321 mg of sodium carbonate was added and a solution of 556 mg of 2-(4-bromobutyloxy)acetic acid tert-butyl ester in 2 ml of acetone was added dropwise while stirring under ice-cooling, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and then the residue was combined with water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 701 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][O:5][CH:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[CH2:3]1.[H][H]>C(OCC)(=O)C.[Pd]>[O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH:4]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[CH2:3]1
Reactant: O=C1C=COC(CN2C(=O)c3ccccc3C2=O)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCOC(CN2C(=O)c3ccccc3C2=O)C1
Yield: 87 %

Procedure:
2-(4-Oxo-3,4dihydro-2H-pyran-2-ylmethyl)-isoindole-1,3-dione (13 g, 0.051 mol) was dissolved in ethyl acetate (250 ml) and placed in a Parr bottle. 10% Pd/C (1.5 g) was carefully added and the mixture was shaken under a pressure of 30 psi of hydrogen for 6.5 h (Parr apparatus). Filtration followed by evaporation of the ethyl acetate in vacuo afforded a crude 11.5 g of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione pure enough for the next step. Analytical pure compound could be obtained by purification of a small sample (250 mg) by column chromatography on silica gel, utilising a mixture of hexane/ethyl acetate as a gradient (from 100/0 to 50/50). Pure fractions were collected and the solvent evaporated in vacuo affording 142 mg (55%) of 2-(4-oxo-tetrahydro-pyran-2-ylmethyl)-isoindole-1,3-dione as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([Si:8]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])(OCC)OCC)=[C:6]([F:26])[C:5]([F:27])=[C:4]([F:28])[C:3]=1[F:29].S(Cl)([Cl:32])=O.[ClH:34].[NH+]1C=CC=CC=1>>[F:1][C:2]1[C:7]([Si:8]([C:15]2[C:20]([F:21])=[C:19]([F:22])[C:18]([F:23])=[C:17]([F:24])[C:16]=2[F:25])([Cl:32])[Cl:34])=[C:6]([F:26])[C:5]([F:27])=[C:4]([F:28])[C:3]=1[F:29]
Reactant: Cl
Reactant: O=S(Cl)Cl
Reactant: CCO[Si](OCC)(c1c(F)c(F)c(F)c(F)c1F)c1c(F)c(F)c(F)c(F)c1F
Agent: c1cc[nH+]cc1
Product: Fc1c(F)c(F)c([Si](Cl)(Cl)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reaction time: 16 h

Procedure:
180.93 g (0.400 mol) di(pentafluorophenyl)diethoxysilane, 146 mL (2.00 mol, 237.9 g) thionylchloride and 4.92 g (0.0426 mol) pyridinium hydrochloride are refluxed and stirred for 16 h. Excess of SOCl2 is evaporated and di(pentafluorophenyl)dichlorosilane isolated by vacuum-distillation.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[NH:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[S:31](Cl)(=[O:33])=[O:32].O>CN(C=O)C>[Cl:3][C:4]1[CH:19]=[CH:18][C:7]2[N:8]([S:31]([C:23]3[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=3[O:21][CH3:20])(=[O:32])=[O:33])[C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)n1c(=O)n(-c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.15 g of sodium hydride as an 80% dispersion in oil was added in portions, with stirring, to a solution of 1.223 g of 5-chloro-1,3-dihydro-3-phenyl-2H-benzimidazol-2-one in 12 ml of DMF at room temperature; 1.384 g of 2-methoxy-4-nitrobenzenesulfonyl chloride were then introduced and the reaction medium was stirred at room temperature for 24 hours. The solvent was then evaporated off under vacuum and the residue obtained was taken up with water. It was then extracted with DCM, washed with water and then dried over sodium sulfate and the solvent was evaporated off to dryness. The residue obtained was chromatographed on silica using a DCM/AcOEt mixture (92/8; v/v) as the eluent to give the expected product in the form of a yellow product, which crystallized from absolute EtOH. m=1.870 g. M.p.>250° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(F)cc1F
Yield: 56 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,4-difluorobenzenesulfonyl chloride (11.7 mg, 0.055 mmol) and 5-(3-amino-phenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 56% yield (9.5 mg). MS (ESI+) calcd mass for C13H9F2N5O2S 337.044502, found 337.044202.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16]CC)=[O:15])[N:5]=2.C1COCC1.O.[OH-].[Li+].Cl>O.CO>[NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([OH:16])=[O:15])[N:5]=2
Reactant: CCOC(=O)c1cccc(-c2ccc3nc(N)sc3n2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc2ccc(-c3cccc(C(=O)O)c3)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
To a solution of ethyl 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoate (400 mg, 1.34 mmol) in a mixture of water (2.0 mL), THF (2.0 mL) and methanol (2.0 mL) was added lithium hydroxide monohydrate (281 mg, 11.85 mmol). The reaction mixture was stirred at room temperature for 16 h and was neutralized with 1N aqueous HCl until pH=6 (monitored with pH paper). The organic solvent was removed in vacuo and the resulting brown solid was collected and dried to give 310 mg (85% yield) of 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)benzoic acid.
Reaction SMILES: [Br:1][C:2]1[C:19]2[C:20]3[C:5]([C:6]4[C:21]5[C:10]6=[C:11]([C:22](O[C:25](=[O:26])[C:9]6=[CH:8][CH:7]=4)=[O:23])[CH:12]=[CH:13][C:14]=5[C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1.[CH2:27]([CH:34]([NH2:42])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN1CCCC1=O.C(O)(=O)C>[CH2:27]([CH:34]([N:42]1[C:25](=[O:26])[C:9]2[C:8]3[C:7]4[C:6](=[CH:21][CH:10]=2)[C:5]2[C:20]5[C:19]([C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:18][CH:17]=[CH:16][C:15]=5[C:14]=4[CH:13]=[CH:12][C:11]=3[C:22]1=[O:23])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C1OC(=O)c2ccc3c4ccc(Br)c5cccc(c6ccc1c2c63)c54
Reactant: CCCCCCCC(N)CCCCCCC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CCCCCCCC(CCCCCCC)N1C(=O)c2ccc3c4cccc5c(Br)ccc(c6ccc(c2c36)C1=O)c54
Temperature: 135 °C

Procedure:
Under protective gas, a mixture of 3 g (7.48 mmol) of 9-bromoperylene-3,4-dicarboxylic anhydride and 8 g (35 mmol) of 1-heptyloctylamine in 150 ml of N-methylpyrrolidone and 3 ml of acetic acid was heated to 135° C. for 20 h.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C[NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1)=[O:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C:16](=[O:17])[NH2:15])[CH:22]=1
Reactant: CNC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
2.84 g (14.07 mmoles) of 4-nitrophenyl chloroformate are added in small portions to a solution of 2.0 g (14.07 mmoles) of 3-methylcarbamoyl-isoxazol-5-yl-methanol (commercial), 1.71 ml (21.11 mmoles) of pyridine and 0.17 g (1.41 moles) of N,N-dimethylaminopyridine in 15 ml of dichloromethane, cooled to about 0° C. The medium is maintained with stirring for 1 hr at 0° C. then for 1 hr at ambient temperature. The precipitate formed is filtered off then copiously rinsed with diisopropyl ether. After drying under vacuum at about 60° C., 3.12 g of the expected product are obtained in the form of a white solid used as such in the following stage.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12].C(N(CC)CC)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[CH2:21][NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[NH2:12])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCc1ccc([N+](=O)[O-])cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 45 %

Procedure:
To a solution of 2-aminomethyl-5-nitro-phenylamine (2.84 g, 17 mmol) in dry THF (150 mL) and triethylamine (12 mL, 85 mmol) was added tert-butyl bromoacetate (5 mL, 34 mmol). The mixture solution was stirred at room temperature for 16 hours and concentrated. Chromatography of the resulting residue on silica gel with methylene chloride and methanol (50:1) gave 2.15 g of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (45%): 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, 1H), 7.55 (5, 1H), 7.22 (d, 1H), 5.2 (br, 2H) 3.95 (s, 2H), 3.39 (s, 2H), 1.58 (s, 9H); MS (m/e): 282.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].[C:34]1(C)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>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.C(O)C>[C:34]1([CH:7]2[O:8][CH2:9][CH2:10][N:5]([CH2:4][C:3]3[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=3[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[C:16]([F:27])([F:26])[F:15])[CH2:6]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccccc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Brc1ccccc1CN1CCOCC1
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: CCO
Product: FC(F)(F)c1ccccc1-c1ccccc1CN1CCOC(c2ccccc2)C1
Temperature: 120 °C

Procedure:
100 mg of 4-(2-Bromo-benzyl)-morpholine was combined with 86 mg of 2-(Trifluoromethyl)phenyl boronic acid, 17 mg of tetrakis(triphenylphosphine)palladium(0), 1.0 mL of 2M sodium carbonate solution, 2.71 mL toluene and 1.4 mL ethanol. The reaction mixture was heated in a sealed tube at 120° C. overnight in an oil bath. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was purified by flash chromatography using flash chromatography using an ethyl acetate/hexanes gradient. 74 mg of product is obtained. ES MS (+) m/z 398
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:28])[F:27])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:38]([S:40]([CH:43]=C)(=[O:42])=[O:41])=[CH2:39].CO>C(Cl)Cl>[CH3:43][S:40]([CH2:38][CH2:39][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:19][CH2:18][CH2:17][C:16]4[N:12]([N:13]=[C:14]([C:20]5[N:21]([CH2:25][C:26]([F:29])([F:27])[F:28])[N:22]=[CH:23][N:24]=5)[CH:15]=4)[C:11]=3[CH:30]=2)[CH2:5][CH2:6]1)(=[O:42])=[O:41]
Reactant: FC(F)(F)Cn1ncnc1-c1cc2n(n1)-c1cc(C3CCNCC3)ccc1OCC2
Reactant: C=CS(=O)(=O)C=C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CS(=O)(=O)CCN1CCC(c2ccc3c(c2)-n2nc(-c4ncnn4CC(F)(F)F)cc2CCO3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A mixture of 9-piperidin-4-yl-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene (90 mg, 0.22 mmol), triethylamine (150 L, and IMS (0.6 mL) was treated with vinyl sulfone (48 mL, 0.54 mmol) then diluted with DCM and stirred for 18 h at RT. The reaction mixture was concentrated in vacuo and the residue triturated in diethyl ether to provide a solid which was subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM) to give 152 as a white solid (96 mg, 85%). 1H NMR (400 MHz, CDCl3): δ 8.01 (s, 1H); 7.69 (s, 1H); 7.19-7.08 (m, 2H); 6.92 (s, 1H); 5.53 (q, J=8.15 Hz, 2H); 4.54 (t, J=6.01 Hz, 2H); 3.21-3.12 (m, 4H); 3.21-2.92 (m, 5H); 2.93 (t, J=6.33 Hz, 2H); 2.63-2.54 (m, 1H); 2.21 (t, J=11.57 Hz, 2H); 1.94 (d, J=12.96 Hz, 2H); 1.81-1.66 (m, 2H). LCMS: RT=6.57 min, M+H+=525
Reaction SMILES: [O:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.[CH3:18][Li].O>C(OCC)C>[OH:1][C:2]1([CH3:18])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1
Reactant: [Li]C
Reactant: O=C1Cc2ccccc2C=Cc2ccccc21
Solvent: CCOCC
Solvent: O
Product: CC1(O)Cc2ccccc2C=Cc2ccccc21

Procedure:
To a stirred solution of 5-oxo-dibenzo[a,e]cyclooctene (10.0 g) in dry diethyl ether at 0° C. under nitrogen, was added over 5 minutes, through a canula, a solution of methyl lithium (40 ml of a 1.4M solution in diethyl ether). After a further 10 minutes stirring water (40 ml) was added cautiously and the separated aqueous layer discarded. The organic layer was washed with water. then dried and evaporated. Crystallisation from diethyl ether/hexane gave the pure alcohol (6.2 g), mp 108°-109° C.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH:12]=[O:13].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-:26].[K+].[K+]>>[CH3:7][N:6]1[C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:23])([F:24])[F:14])=[CH:21][CH:20]=2)=[C:3]([C:12]([OH:13])=[O:26])[C:4]([C:8]([F:11])([F:10])[F:9])=[N:5]1
Reactant: Cn1nc(C(F)(F)F)c(C=O)c1Cl
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: Cn1nc(C(F)(F)F)c(C(=O)O)c1Oc1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared using 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde and 4-(trifluoromethyl)phenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]([NH2:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[CH2:13][C@H:12]1[C:17]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)OCc1ccccc1

Procedure:
Benzyl-(2S,4S)-2-aminocarbonyl-4-fluoropyrrolidine-1-carboxylate in dichloromethane was treated at 0° C. with Et3N (2.1 eq.) and trifluoroacetic anhydride was added dropwise.