Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN([CH:29]=[O:30])C>>[CH2:1]([C:8]1[C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[C:16]([Br:17])[C:11]=2[O:10][C:9]=1[CH:29]=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)c2occ(Cc3ccccc3)c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)c2oc(C=O)c(Cc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 61 %

Procedure:
3-Benzyl-7-bromo-5-methyl-benzofuran (3.93 g, 13.05 mmol) was mixed with 10 ml DMF. Phosphorus oxychloride (1.8 ml, 19.3 mmol) was added and the reaction mixture was heated to 50° C. for 16 hours. Additional phosphorus oxychloride (3.6 ml, 38.6 mmol) was added and the reaction mixture was heated to 90° C. for an hour, then to 100° C. for five hours. The mixture was cooled to room temperature, poured onto ice and aqueous sodium hydroxide was added until the mixture reached pH=3. The mixture was extracted with ethyl acetate, dried over magnesium sulfate, filtered, and absorbed onto 20 gm silica gel. The silica gel was layered over 100 gm silica gel in a fritted funnel and eluted with five portions of 400 ml hexanes (to give 0.33 g recovered starting material) and two portions of 400 ml of 10/90 ethyl acetate/hexane to give 3-benzyl-7-bromo-5-methyl-benzofuran-2-carbaldehyde (2.61 g, 61% yield). MS: (M+H)+ 330.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:14])[C@@H:10](Br)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:15]=[N+:16]=[N-:17].[Na+].O.C([O-])(O)=O.[Na+]>CN(C)C=O>[N:15]([C@H:10]([CH2:11][OH:12])[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:14])=[N+:16]=[N-:17]
Reactant: O=C(NCc1ccccc1)[C@@H](Br)CO
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 52.5 °C
Yield: 99.62 %

Procedure:
To a reaction flask was charged (2S)-N-benzyl-2-bromo-3-hydroxypropanamide (80.0 g) and sodium azide (30.23 g) in N,N-dimethylformamide (480 ml) and raised the temperature to 50-55° C. and maintained for 4-5 hours. Stopped heating and cooled the reaction mixture to 20-25° C. and charged DM water (400 ml), adjusted pH of the reaction mixture to 9-9.5 using 5% NaHCO3 solution. Extracted the reaction mass with ethyl acetate (1×800 ml, 2×280 ml). Separated the organic layer and combined all ethyl acetate layers, washed with saturated ammonium chloride solution (2×240 ml). Concentrated the solvent ethyl acetate under reduced pressure to get oily compound of (2R)-2-azido-N-benzyl-3 -hydroxypropanamide.
Reaction SMILES: [F:1][CH:2]([F:13])[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[NH:6][C:5](=[O:12])[CH:4]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:13][CH:2]([F:1])[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH3:11])[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:5](=[O:12])[CH:4]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc(C(F)F)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc(C(F)F)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39 %

Procedure:
A mixture of 6-(difluoromethyl)-2-propylpyrimidin-4(3H)-one (5.6 g), 4′-(bromomethyl)biphenyl-2-carbonitrile (9 g) and potassium carbonate (8.3 g) in acetonitrile (60 mL) was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale yellow solid (4.4 g, 38%).
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:21]=[N:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[O:30]1[CH2:33][CH:32]([NH2:34])[CH2:31]1>>[O:30]1[CH2:33][CH:32]([NH:34][C:15]([C:14]2[CH:18]=[CH:19][N:20]=[CH:21][C:13]=2[NH:12][C:10]([C:8]2[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:9]=2)=[O:11])=[O:16])[CH2:31]1
Reactant: NC1COC1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Agent: Cl
Product: O=C(NC1COC1)c1ccncc1NC(=O)c1nc(C2CC2)cnc1Nc1cncnc1
Yield: 58 %

Procedure:
According to the procedure described in step 3 of example 99, 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-isonicotinic acid (example 99, step 2) was reacted with oxetan-3-amine hydrochloride, providing the title compound as yellow solid (58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:23])[C:16]([C:18](OCC)=[O:19])=[CH:17][N:11]3[CH:10]3[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH:14]=1.O.[NH2:25][NH2:26]>CO>[OH2:19].[F:1][C:2]1[CH:3]=[C:4]2[C:12]3=[C:13]([C:15](=[O:23])[C:16]([C:18]([NH:25][NH2:26])=[O:19])=[CH:17][N:11]3[CH:10]3[CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9]3)[CH:14]=1
Reactant: NN
Reactant: CCOC(=O)c1cn2c3c(cc(F)cc3c1=O)C1CCCCC12
Solvent: CO
Solvent: O
Product: NNC(=O)c1cn2c3c(cc(F)cc3c1=O)C1CCCCC12

Procedure:
2 g of ethyl 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylate was dissolved in 80 ml of methanol, and 5 ml of hydrazine hydrate was added thereto. The mixture was then heated while refluxing. The precipitated yellow needle crystals were separated by filtration, and recrystallized from ethanol to obtain 1.7 g of 2-fluoro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carbohydrazide monohydrate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[CH3:10][Zn]C>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.CN(C=O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([CH3:10])[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: C[Zn]C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nnc1N
Temperature: 25 °C
Yield: 100.6 %

Procedure:
A 100 mL flask was charged with 4-bromo-6-chloropyridazin-3-amine (1 g, 4.80 mmol), dimethylzinc (9.59 mL, 9.59 mmol), Pd(PPh3)4 (0.277 g, 0.240 mmol) and DMF (10 mL). The reaction mixture was stirred at RT. Then the reaction mixture was quenched with MeOH and concentrated. The crude product was loaded onto a 10 g SCX SPE, and 3 volumes of MeOH followed by 3 volumes of 2N ammonia in MeOH were added. The fractions were combined and concentrated to afford 6-chloro-4-methylpyridazin-3-amine (693 mg, 80% yield).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:9]([Si:11]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10]>>[Si:11]([CH2:9][CH2:10][P:1]([O:5][CH2:6][CH3:7])([O:2][CH2:3][CH3:4])=[O:8])([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]
Reactant: CCOP([O-])OCC
Reactant: C=C[Si](OCC)(OCC)OCC
Product: CCO[Si](CCP(=O)(OCC)OCC)(OCC)OCC
Yield: 33 %

Procedure:
Compounds of Formula II can be synthesised via a free radical promoted addition of a dialkyl phosphite to vinyl trialkoxy silane and then distillation, according to the procedure of G. H. Barnes and M. P. David in J. Org. Chem., 25, 1191, (1960). In this paper Barnes and David reported the synthesis of a number of organosilicon phosphonate esters and acids. They utilised known procedures for the free radical addition of dialkyl phosphites to double bonds. The state of this art is described in Org. Reactions. Vol. 13, 218-222. They reacted diethyl phosphite with vinyl triethoxy silane at 120-130° C. in the presence of a free radical initiator. The desired product, (EtO)3SiCH2CH2PO(OEt)2, was obtained after careful distillation in 33% yield.
Reaction SMILES: [CH:1](OCC)=[O:2].[CH2:6]([NH:9][CH2:10][CH:11]=[CH2:12])[CH:7]=[CH2:8].N#N>>[CH2:6]([N:9]([CH2:10][CH:11]=[CH2:12])[CH:1]=[O:2])[CH:7]=[CH2:8]
Reactant: CCOC=O
Reactant: C=CCNCC=C
Agent: N#N
Product: C=CCN(C=O)CC=C
Temperature: 120 °C
Yield: 95 %

Procedure:
Ethyl formate (55.6 g, 750 mmole) and 37.5 g (385 mmole) of N,N-diallyl amine were combined in a 250 mL 3-neck flask equipped with mechanical stirrer, Friedrich condenser, and N2 blanket. The reaction mixture was stirred at reflux temperature (120° C. oil bath) for 24 hours and then sampled by GC to determine if all the N,N-diallylamine was reacted, RT of 0.4 mm. The product was vacuum distilled using a 1-piece apparatus with a fractionation column. The first fraction distilled at 30° C./16 torr. The second fraction N,N-diallylformamide (NDF), distilled at 88°-90° C./10-14 torr. The yield was 95%. Structure was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C:7](=O)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32]([SH:35])[CH2:33][SH:34].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:8][C:7]2([S:35][CH2:32][CH2:33][S:34]2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:20]
Reactant: SCCS
Reactant: COC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2

Procedure:
Dissolve 7.0 g of 1-benzyloxycarbonyl-4-keto-(S)-proline methyl ester in 75 ml of glacial acetic acid. Add 0.7 g of p-toluenesulfonic acid and 2.8 g of 1,2-ethanedithiol and heat under reflux with stirring for eighteen hours. Add the reaction mixture to saturated sodium bicarbonate solution and extract with ethyl acetate. Dry the organic layer over magnesium sulfate and concentrate it. Place the residue on a column of silica gel (300 g, 60-200 mesh) and elute with hexane:ethyl acetate (1:1) to give 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro-[4.4]nonane-8(S)-carboxylic acid methylester, a yellow oil having [α]D26 -12.6° (dioxane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCOC(=O)C(C)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(N)c(OC)c1
Reaction time: 15 h
Yield: 74.2 %

Procedure:
To a stirred solution of ethyl 2-(3-methoxy-4-nitrophenyl)propanoate (683 mg, 2.697 mmol) in tetrahydrofuran and ethanol as co-solvent were added 10% Pd/C (70 mg). The mixture was charged with H2 (gas) balloon. The resulting mixture was stirred for 15 h, then filtered using celite. The filtrate removed in vacuo. The crude was purified by column chromatography. Ethyl 2-(4-amino-3-methoxyphenyl)propanoate (447 mg) was obtained as 74% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]=[C:11]=[N:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:11]3[N:10]([C:4]4[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cc(C)ccc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C)ccc1OC

Procedure:
Starting from 91 mg (0.28 mmol) of the carbodiimide from Example 16A and 76 mg (0.42 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative HPLC result in 14 mg (9% of theory) of product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH:17]([N:20]1[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:24]2[N:20]([CH:17]([CH3:19])[CH3:18])[N:21]=[CH:22][CH:23]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C(C)C
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C(C)C)c(C(F)(F)F)cc1N
Temperature: 100 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
To a solution of 2-amino-4-trifluoromethyl-5-iodo-benzoic acid methyl ester (1.56 g, 4.52 mmol) in dioxane (40 mL) were added 1-isopropyl-5-tributylstannanyl-1H-pyrazole (2.34 g, 1.3 eq) and Pd(dppf)2Cl2 (369 mg, 0.1 eq) and the resulting mixture was stirred at 100° C. for 18 h. A second portion of catalyst (0.1 eq) was added and the mixture was stirred at 100° C. for 24 h. A last portion of catalyst (0.1 equiv) was added and the mixture was kept at 100° C. for 72 h. The solvent was removed in vacuo to provide a dark oil which was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to give the title compound (666 mg, 45%) as an off-white solid (ES-MS: m/z 328.3 [M+H]+, rt 5.60 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2Cl.[OH-].[NH4+:15].N>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[NH2:15]
Reactant: [NH4+]
Reactant: Clc1nc(Cl)c2cccc(Br)c2n1
Agent: N
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(Cl)nc2c(Br)cccc12
Reaction time: 1 h
Yield: 68 %

Procedure:
To a slurry of 8-bromo-2,4-dichloroquinazoline (407b; 0.50 g, 1.80 mmol) in 2 mL THF at 0° C. was added ammonium hydroxide, 28% ammonia in water (3.25 mL, 23.39 mmol). The reaction was sealed and the ice/water bath was removed. The heterogeneous reaction was stirred rapidly. In the morning starting material was still evident. 2 mL THF and 1 mL 28% ammonia in water were added and the reaction became homogeneous. After 1 h, reaction was checked and judged complete. The reaction was partitioned between water and DCM. The layers were separated and the aqueous layer was filtered through Celite and the filtrate was extracted 2×DCM and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 8-bromo-2-chloroquinazolin-4-amine (0.318 g, 1.23 mmol, 68% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.52 (2H, br. s.), 8.24 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=7.6 Hz), 7.42 (1H, t, J=7.9 Hz). m/z (ESI, +ve ion) 257.9/259.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[C:10]1([CH:20]=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>CS(O)(=O)=O>[F:1][C:2]1[C:3](=[O:9])[CH:4]=[C:5]2[C:7](=[CH:8][C:7]3[C:5]([O:6]2)=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:8]=3)[C:20]=1[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: Oc1ccc(F)c(O)c1
Agent: CS(=O)(=O)O
Product: O=c1cc2oc3cc(O)c(F)cc3cc-2c(-c2cccc3ccccc23)c1F

Procedure:
Two equivalents of 4-fluororesorcinol (Compound 15) are condensed with one equivalent of naphthalene-1-carboxaldehyde in warm methanesulfonic acid. When the reaction is judged complete by TLC analysis, the intermediate product is precipitated from the reaction solution by the addition of an excess of water. The crude solid is collected on a Buichner funnel, and dried in vacuo. The intermediate is then dissolved in chloroform and treated with an excess of chloramine-T. When the oxidation reaction is complete, as judged by TLC, the volatiles are removed in vacuo and the crude product is purified using flash chromatography to give Compound 57.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=1.C(N(CC)CC)C.[Cl:37][CH:38]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:39](Cl)=[O:40]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]([N:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[C:39](=[O:40])[CH:38]([Cl:37])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([CH3:18])[CH2:9][O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:12])[CH3:13])[CH:7]=1
Reactant: COc1ccc(CN[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Reactant: O=C(Cl)C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN(C(=O)C(Cl)c2ccccc2)[C@@](C)(CO[Si](C)(C)C(C)(C)C)c2cc(Br)ccc2F)cc1
Temperature: 10 °C
Reaction time: 3 h

Procedure:
A solution of [(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-(4-methoxy-benzyl)-amine (1.035 g, 2.15 mmol) in acetonitrile (16 ml) was treated with triethylamine (0.36 ml, 2.57 mmol). The mixture was cooled to 10° C. and a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.34 ml, 2.36 mmol) in acetonitrile (2 ml) was added slowly. The reaction mixture was allowed to warm to room temperature and was stirred for 3 hours. Because the transformation was not complete, triethylamine (0.33 ml, 2.36 mmol) was again added, the reaction mixture cooled to −5° C., then treated with a solution of (RS)-2-chloro-2-phenyl-acetyl chloride (0.31 ml, 2.15 mmol) in acetonitrile (1 ml). The reaction mixture was allowed to warm to room temperature and was stirred for 22 hours. Thereafter, the mixture was evaporated at reduced pressure and without further workup directly purified by chromatography on Silicycle-Si-amine column using a gradient of heptane and ethyl acetate=100/0 to 70/30 as the eluent. (RS)-N-[(R)-1-(5-bromo-2-fluoro-phenyl)-2-(tert-butyl-dimethyl-silanyloxy)-1-methyl-ethyl]-2-chloro-N-(4-methoxy-benzyl)-2-phenyl-acetamide was obtained as a white foam (1.068 g, 78% of theory). Mass (calculated) C31H38BrClFNO3 [635.09]; (found) [M+H]+=638, [M+2-H]+=636, [M+4-H]+=634.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:26]([O-])=O)=[C:5]([CH:23]=[CH:24][CH:25]=1)[CH2:6][N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:4]1[C:3]([O:2][CH3:1])=[CH:25][CH:24]=[CH:23][C:5]=1[CH2:6][N:7]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:8](=[O:16])[C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1
Reactant: [H][H]
Reactant: CCOC(=O)CN(Cc1cccc(OC)c1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(Cc1cccc(OC)c1N)C(=O)c1ccc(Cl)cc1

Procedure:
1.8 g (4.4 mmol) of ethyl [(3-methoxy-2-nitrobenzyl)-(4-chlorobenzoyl)amino]acetate was dissolved in a mixture of 10 ml of ethyl acetate and 10 ml of ethanol. 180 mg of 10% palladium/carbon was added to the obtained solution, and they were stirred in the presence of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through Celite and the solvent was evaporated. The obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C([NH:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH:11]2[CH:10]1[CH3:24])C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2]>[NH2:8][CH:9]1[CH2:23][CH:12]2[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:20])[CH3:22])=[O:17])[CH2:15][CH:11]2[CH:10]1[CH3:24]
Reactant: [H][H]
Reactant: CC1C(NCc2ccccc2)CC2CN(C(=O)OC(C)(C)C)CC21
Agent: [Pd+2]
Agent: [OH-]
Product: CC1C(N)CC2CN(C(=O)OC(C)(C)C)CC21
Yield: 107.4 %

Procedure:
A mixture of tert-butyl 5-(benzylamino)-4-methylhexahydrocyclopenta-[c]pyrrole-2(1H)-carboxylate (13.2 g, 39.9 mmol) and 20% palladium hydroxide on carbon (4.21 g, 5.99 mmol) was stirred under 30 psi hydrogen for 5 h. The mixture was filtered through a celite pad to remove the solid catalyst. The filter cake was rinsed with methanol. The filtrate was concentrated to give crude tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (10.3 g) as an approximately 3:1:1 mixture of three isomers. The material was taken to the next step without further purification. MS (ES+) m/z: 241.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:16][C:6]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:8]=3[NH:9][C:5]=2[CH2:4][CH2:3]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][C:2]1([CH3:17])[CH:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:6]2[C:7]3[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][C:8]=3[NH:9][C:5]=2[CH2:4][CH2:3]1
Reactant: CCCCCCCCBr
Reactant: CC1(C)CCc2[nH]c3cc(C#N)ccc3c2C1
Product: CCCCCCCCC1c2c([nH]c3cc(C#N)ccc23)CCC1(C)C
Yield: 108.3 %

Procedure:
Using the procedure of Example 9, 5.6 g of the carbonitrile from Example 5 was alkylated with 6.35 g of 1-bromooctane to give 9.1 g (96.4%) of 5,6,7,8-tetrahydro-8,8-dimethyl-9-octyl-9H-dibenzo[b,d]pyrrole-3-carbonitrile as a yellow oil. This material was used without purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:14]([C:15]3[CH:19]=[CH:18][O:17][N:16]=3)[N:4]2[N:3]=1.[OH:20][CH2:21][C:22]1[N:23]=[N:24][N:25]([CH2:27][CH3:28])[CH:26]=1>>[CH2:27]([N:25]1[CH:26]=[C:22]([CH2:21][O:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]3=[N:12][N:13]=[C:14]([C:15]4[CH:19]=[CH:18][O:17][N:16]=4)[N:4]3[N:3]=2)[N:23]=[N:24]1)[CH3:28]
Reactant: CCn1cc(CO)nn1
Reactant: Clc1nn2c(-c3ccon3)nnc2c2ccccc12
Product: CCn1cc(COc2nn3c(-c4ccon4)nnc3c3ccccc23)nn1

Procedure:
The title-compound was prepared from 6-chloro-3-(3-isoxazolyl)-1,2,4-triazolo[3,4-a]phthalazine (prepared as described in Example 34, step b) and 4-hydroxymethyl-1-ethyl-1,2,3-triazole (prepared as described in Example 98 part a), following the procedure described in Example 98, but performing the reaction at −45° C. 1H NMR (360 MHz, CDCl3) δ 1.55 (3H, t, J=7.5 Hz, CH3), 4.40 (2H, q, J=7.4 Hz, CH2), 5.78 (2H, s, CH2), 7.31 (1H, d, J=1.7 Hz, Ar—H), 7.82 (1H, m, Ar—H), 7.95 (1H, m, Ar—H), 8.27 (1H, d, J=7.8 Hz, Ar—H), 8.64-8.66 (2H, m, 2 of Ar—H), 8.69 (1H, s, Ar—H); MS (ES30) m/e 363 [MH]+; Anal. Found. C, 56.24; H, 3.70; N, 30.65. C17H14N8O2 requires C, 56.35; H, 3.89; N, 30.92%.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=O.CO.Cl.[NH2:17][OH:18]>O>[CH3:1][NH:2][C:3](=[O:13])[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[N:17][OH:18]
Reactant: NO
Reactant: CNC(=O)C(=O)c1ccccc1C
Agent: Cl
Solvent: CO
Solvent: O
Product: CNC(=O)C(=NO)c1ccccc1C

Procedure:
To N-methyl-2-(2-methylphenyl)-2-oxoacetamide (5.31 g, 0.03 mol), added were methanol (30 ml) and hydroxylamine hydrochloride (4.17 g, 0.06 ml), and the reaction mixture was heated under reflux for 5 hours. After completion of the reaction, water (150 ml) was added to the reaction mixture which was then extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give N-methyl-2-(2-methylphenyl)-2-hydroxyiminoacetamide in E-form (4.79 g; yield, 83.1%) and Z-form (0.50 g; yield, 8.7%) as colorless crystals.