Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([S:6](Cl)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:10]>CO>[CH:1]1([S:6]([NH2:10])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N
Reactant: O=S(=O)(Cl)C1CCCC1
Solvent: CO
Product: NS(=O)(=O)C1CCCC1
Yield: 66 %

Procedure:
According to Reference Example 9-7, by use of cyclopentanesulfonyl chloride (300 mg, 1.8 mmol) and a 7 mol/L solution of ammonia in methanol (2 mL), the mixture was stirred and reacted at room temperature for 4 hours. After slurry purification using chloroform, purification by silica gel column chromatography (chloroform/methanol=1/0 to 20/1) was performed to give cyclopentanesulfonamide (Compound FP) (173 mg, yield: 66%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:39][C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[C:42]([O:49][C@H:50]([CH2:52][CH:53]=[CH2:54])[CH3:51])[CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.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>[CH2:1]([O:4][C:5]1([CH3:38])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:43]5[CH:44]=[CH:45][C:40]([F:39])=[CH:41][C:42]=5[O:49][C@H:50]([CH2:52][CH:53]=[CH2:54])[CH3:51])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:27])[C:12]=2[C@H:28]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]([O:31][CH3:32])=[O:30])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1B(O)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Temperature: 90 °C
Yield: 66.5 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.27 g, 0.462 mmol, 1 equiv) and (S)-(4-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid (207 mg, 0.924 mmol, 2 equiv) in DMF (5 mL, sparged with nitrogen for 10 min) was added Pd(PPh3)4 (53 mg, 0.046 mmol, 0.1 equiv) and 2 M Na2CO3 (0.46 mL, 0.924 mmol, 2 equiv). The reaction was heated at 90° C. for 2.5 h. Upon cooling to ambient temperature, the reaction was diluted with EtOAc, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (210 mg, 66%) as a viscous yellow oil. LCMS (ESI, M+1): 684.35.
Reaction SMILES: [C:1]([C:3](=[CH:6][N:7]([CH3:9])[CH3:8])[CH:4]=O)#[N:2].[NH2:10]OS(O)(=O)=O.[OH-].[Na+]>O>[CH3:8][N:7]([CH:6]=[C:3]([C:4]#[N:10])[C:1]#[N:2])[CH3:9]
Reactant: NOS(=O)(=O)O
Reactant: CN(C)C=C(C#N)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)C=C(C#N)C#N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a slurry of 12.4 g. of 2-cyano-3-dimethylaminoacrolein in 50 ml. of water was added in small portions 13.6 g. of hydroxylamine-0-sulfonic acid (91% pure). The resulting clear solution was stirred for an additional 10 minutes, then cooled to 0° and adjusted to pH 6.0 by addition of approximately 26 ml. of 5N sodium hydroxide solution. The mixture was heated for 20 minutes in a water bath at 70°. A pH 3 was maintained over this period by dropwise addition of 5N sodium hydroxide solution. After cooling to room temperature, the mixture was extracted with 3 × 100 ml. of methylene chloride. The combined extracts were washed with 50 ml. of water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Thus, dimethylaminomethylenemalononitrile was obtained. After recrystallization from isopropanol, the material had a melting point of 93°-95°.
Reaction SMILES: C(O[CH:5]([CH2:11][CH:12]([CH3:24])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH:6]([N+:8]([O-:10])=[O:9])[CH3:7])(=O)C.CC(C)([O-])C.[K+].CCOCC.O>C(O)(C)(C)C>[CH3:24][CH:12]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:23])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:11][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH3:7]
Reactant: CC(=O)OC(CC(C)CCC=C(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: CC(C)=CCCC(C)=CCCC(C)CC=C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.4 %

Procedure:
A solution of 1.30 g of 5 in 25 mL of t-butyl alcohol was added to a solution of 30 mL of t-butyl alcohol containing 0.53 g of potassium t-butoxide. The reaction mixture was stirred at room temperature for 1 h, whereupon it was added to 150 mL of ether and 20 mL of H2O. The organic layer was separated and dried over MgSO4, and the solvent was removed by rotary evaporation to afford 0.40 g of racemic RG-4, predominantly the (E)-isomer. 1H NMR δ (ppm) 7.18 (t, CH═CNO2), 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 2.19 (s, C═C(CH3)NO2), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 2.2-2.3 (m, CH2C═CNO2), (CH3C═(CH3), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)[CH3:3].[Br:13][C:14]1[C:15](=[O:24])[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[CH:18][C:19]=1Br.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Br:13][C:14]1[C:15](=[O:24])[N:16]([CH:21]([CH3:22])[CH3:23])[N:17]=[CH:18][C:19]=1[NH:10][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([O:4][CH2:2][CH3:3])=[CH:6][CH:7]=1
Reactant: CC(C)n1ncc(Br)c(Br)c1=O
Reactant: CCOc1ccc(CN)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOc1ccc(CNc2cnn(C(C)C)c(=O)c2Br)cc1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 0.38 g of 4-ethoxybenzylamine hydrochloride, 0.4 g of 4,5-dibromo-2-iso-propyl-3(2H)pyridazinone, 0.34 g of potassium carbonate, 6 ml of 1,4-dioxane and 18 ml of water, was heated at 90° C. under stirring for 10 hours. The sovent was distilled off under reduced pressure, and water was added to the residue thereby obtained, and the mixture was extracted with ethyl acetate. The extract was washed with diluted hydrochloric acid and a saturated sodium chloride aqueous solution, and dried over sodium sulfate, and then the solvent was distilled off. The product was crystallized from ether to obtain 220 mg of the above identified compound having a melting point of from 151° to 152.5° C. as pale yellow crystals.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][C@@H:5]2[O:6][C:7]3[C:12]([CH2:13][CH2:14][CH2:15][C:16](O)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:4]2[C@H:3]1/[CH:20]=[CH:21]/[C@@H:22]([OH:29])[CH:23]([CH3:28])[CH2:24][C:25]#[C:26][CH3:27].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.[Cl-].[NH4+]>CN(C)C=O>[OH:1][C@@H:2]1[CH2:19][C@@H:5]2[O:6][C:7]3[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:11][CH:10]=[CH:9][C:8]=3[C@@H:4]2[C@H:3]1/[CH:20]=[CH:21]/[C@@H:22]([OH:29])[CH:23]([CH3:28])[CH2:24][C:25]#[C:26][CH3:27]
Reactant: CC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2c3cccc(CCCC(=O)O)c3O[C@H]2C[C@H]1O
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC#CCC(C)[C@H](O)/C=C/[C@@H]1[C@H]2c3cccc(CCCCN4CCOCC4)c3O[C@H]2C[C@H]1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
10 mg of (1R,2R,3aS,8bS)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(3S,1E)-3-hydroxy-4-methyl-1-octene-6-ynyl]-5-(3-carboxypropyl)-1H-cyclopenta[b]benzofuran was taken and was dissolved in 2 mL of dimethylformamide. After addition of 8.1 mg of 1,1′-carbonyldiimidazole, it was stirred at 50° C. for 1 hour. It was cooled to ambient temperature, and 50 mg morpholine was added. After stirring at 50° C. for 1 hour, an aqueous solution saturated with ammonium chloride was added and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, and dried with anhydrous sodium sulfate. After filtration and concentration, 2 mL of tetrahydrofurane was added. While stirring on ice, 9.5 mg of lithium aluminium hydride was added and stirring continued at 0° C. for 15 minutes, then at 50° C. for 1 hour. While stirring at ambient temperature, 100 μL of an aqueous solution saturated with sodium sulfate was added, then 400 mg of anhydrous sodium sulfate was added, and stirred for 1 hour. A filtration was performed over celite, and after washing the residue with ethyl acetate, the filtrate was concentrated and subjected to a silicagel column chromatography, to obtain 5.3 mg of the compound presented in the title (48% yield).
Reaction SMILES: [C:1]1([C:20]([OH:22])=[O:21])[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[C:6]([C:14]([OH:16])=[O:15])[C:5]=2[C:4]([C:17](O)=[O:18])=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O)(=O)C>O>[C:31]1([N:30]=[C:17]([C:4]2[C:5]3[C:6]([C:14]([OH:16])=[O:15])=[CH:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[C:10]=3[C:1]([C:20]([OH:22])=[O:21])=[CH:2][CH:3]=2)[OH:18])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc(C(=O)O)c2c(C(=O)O)ccc(C(=O)O)c12
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(C(=O)O)c2c(C(O)=Nc3ccccc3)ccc(C(=O)O)c12
Temperature: 25 °C
Yield: 83 %

Procedure:
53.6 g of naphthalene-1,4,5,8-tetracarboxylic acid dianhydride (0.2 mol) or 60.8 g of naphthalene-1,4,5,8-tetracarboxylic acid (0.2 mol) are dissolved in 1 l of water at 90° C. with addition of 84 g of triethylamine (0.9 mol), treated with 18.6 g of aniline (0.2 mol) with stirring and adjusted to pH 6 by dropwise addition of about 20 ml of glacial acetic acid at 90° C. The mixture is stirred for about 8 hours at 90° C., the pH value being maintained between 7 and 6 by further dropwise addition of glacial acetic acid (6 ml in total). The mixture is cooled to room temperature, a few undissolved components are filtered off, and the filtrate is adjusted to pH 1 by dropwise addition of about 160 ml of concentrated hydrochloric acid. The crystalline precipitate is filtered off by suction, washed with water until the washings have pH 5, and dried at 70° C. in vacuo. 63 g (87% of theory) of naphthalene-1,4,5,8-tetracarboxylic acid monophenylimide are obtained as an almost colourless crystalline powder of melting point >300° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br.C(N(C(C)C)CC)(C)C>C(#N)C.ClCCl>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1nnc(NC2CCNCC2)s1
Reactant: Fc1ccc(CBr)cc1F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(CN2CCC(Nc3nnc(C(F)(F)F)s3)CC2)cc1F
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 79.3 %

Procedure:
A mixture of piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D4) (0.040 g, 0.16 mmol), 3,4-difluorobenzyl bromide (0.024 ml, 0.19 mmol) and diisopropylethylamine (0.042 ml, 0.24 mmol) in acetonitrile (3 ml) was stirred at 100° C. for 5 min., under microwave irradiation. After cooling to room temperature, the reaction mixture was diluted with dichloromethane and extracted with a 10% solution of ammonium chloride (25 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 0-3% ammonia in methanol (7M)/dichloromethane) to yield E5 (0.048 g, 80%) as a solid. C15H15F5N4S requires 378. Found 379 (MH+).
Reaction SMILES: C([O:5][C:6](=[O:48])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][C@H:14]([NH:28][C:29](=[O:45])[CH2:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([NH:37]C(OC(C)(C)C)=O)[CH2:33][CH2:32]2)[B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[C:8]=1[O:46][CH3:47])(C)(C)C.Cl.C(OCC)C>O1CCOCC1>[NH2:37][C@H:34]1[CH2:35][CH2:36][C@H:31]([CH2:30][C:29]([NH:28][C@H:14]([B:15]2[O:23][CH:22]3[C:17]([CH3:27])([CH:18]4[CH2:24][CH:20]([CH2:21]3)[C:19]4([CH3:26])[CH3:25])[O:16]2)[CH2:13][C:9]2[C:8]([O:46][CH3:47])=[C:7]([CH:12]=[CH:11][CH:10]=2)[C:6]([OH:48])=[O:5])=[O:45])[CH2:32][CH2:33]1
Reactant: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1c(C[C@H](NC(=O)C[C@H]2CC[C@H](N)CC2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To tert-butyl 3-((2R)-2-(2-(tran-4-(tert-butoxycarbonylamino)cyclohexyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate from Step 1 of Example 6 (640 mg) was added 4 N HCl in dioxane (4 mL). The resultant reaction mixture was stirred at RT for 1 hr. Diethyl ether was added to precipitate out the product as while solid (500 mg) which was used directly to the next step.
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:16][OH:17])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2.N1C=CC=CC=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>O.O1CCCC1>[C:24]([O:1][CH2:2][C:3]1([CH2:16][O:17][C:33](=[O:36])[CH2:34][CH3:35])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCC(=O)Cl
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CCC(=O)OCC1(COC(=O)c2ccccc2)c2ccccc2-c2ccccc21
Temperature: 25 °C
Yield: 79 %

Procedure:
To 4.5 g (0.02 mol) 9,9-di(hydroxymethyl)fluorene were added 30 ml tetrahydrofuran, and added 3.3 ml (0.03 mol) pyridine with stirring. To the resulting homogenous mixture was added slowly 2.3 ml (0.02 mol) benzoyl chloride, and the mixture was stirred at temperature for 1 hour, then heated refluxing for 5 hours. Next, the mixture was cooled to room temperature, and 20 ml tetrahydrofuran and 3.3 ml(0.03 mol) pyridine were added with stirring. To the resulting homogenous mixture was slowly added 1.8 ml (0.02 mol) propionyl chloride, and the mixture was stirred at room temperature for 1 hour, and heated refluxing for 5 hours. Then 30 ml water was added to dissolve the resulting salt. The mixture was extracted with toluene. The organic phase was separated, washed with saturated saline for two times, and dried over anhydrous sodium sulfate. The solvent was removed. Recrystallization from ethyl acetate gave 9-(benzoyloxymethyl)-9-(propionyloxymethyl)fluorene as a white crystal, and the yield was 79%. 1HNMR: δ (ppm) 1.23(t, 3H, CH3), 2.39(m, 2H, CH2), 4.48(s, 2H, COOCH2), 4.62(s, 2H, OCH2 linking with benzoyl), 7.33-8.03(m, 13H, ArH)
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:4]=1.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC#N>[Br-:1].[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P+:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[N:4][CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: BrCc1ccc(-c2ccccc2)cn1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: [Br-]
Product: c1ccc(-c2ccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2)cc1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To the bromide (step 2) (100 mg) in CH3CN (2 cc) was added triphenylphosphine (400 mg) and the mixture was heated at 70° C. for 1.5 hours. The solvent was removed in vacuo and replaced by Et2O (3 cc) and toluene (3 cc). The resulting solid was swished for 3 hours, filtered and dried to afford the title compound, used as such in the next step.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH:14]=[CH:13][N:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I.O>CCCCCC.CN(C)C=O>[C:3]([O:7][C:8]([N:10]([C:11]1[CH:16]=[C:15]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH:14]=[CH:13][N:12]=1)[CH3:26])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
60% Sodium hydride (310 mg, 7.6 mmol) was washed with hexane (5.0 mL), and the residue was suspended in N,N-dimethylformamide (20 mL). 2-tert-Butoxycarbonylamino-4-(tert-butyldimethylsilyloxymethyl)pyridine (Reference compound No. 5-1, 1.3 g, 3.7 mmol) was added dropwise to the suspension for 15 minutes under ice-cooling, and methyl iodide (2.4 mL, 39 mmol) was added thereto, and then the mixture was stirred overnight at room temperature. Water (70 mL) was added to the reaction suspension, and the whole was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (100 mL), and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure to give 1.4 g of the mixture including the title reference compound as an orange-red oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](Cl)([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1>ClCCl>[CH3:49][O:48][C:45]1[CH:44]=[CH:43][C:42]([C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH:17][C:10]2[CH2:11][O:12][CH2:13][C:14]([F:16])([F:15])[C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=2)=[CH:47][CH:46]=1
Reactant: C[C@]1(c2cc(Br)ccc2F)N=C(N)COCC1(F)F
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 2 h

Procedure:
To a solution of (R)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A7.1) (9.0 mmol) in dichloromethane (150 ml) was subsequently added at 0° C. triethylamine (18.0 mmol) and 4,4′-dimethoxytriphenylmethyl chloride (9.9 mmol) and stirring was continued at 22° C. for 2 hours. For the workup, the mixture was washed with saturated an aqueous solution of ammonium chloride. The organic layer was dried, evaporated at reduced pressure, and the residue was purified by chromatography on silica using cyclohexane/ethyl acetate to give pure (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (A8.1) as a colorless foam. MS (ISP): m/z=639.3 [M+H]+ and 641.4 [M+2+H]+.
Reaction SMILES: S([O-])(O)=O.[Na+].[NH2:6][C:7]1[C:12]([CH:13]=O)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=2)=[CH:9][N:8]=1.[NH2:29][C:30]1[CH:31]=[C:32]([C:37]2[CH:38]([CH3:44])[CH2:39][C:40](=[O:43])[NH:41][N:42]=2)[CH:33]=[CH:34][C:35]=1[NH2:36].O>CN(C=O)C>[NH2:6][C:7]1[C:12]([C:13]2[NH:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:38]([CH3:44])[CH2:39][C:40](=[O:43])[NH:41][N:42]=4)[CH:33]=[CH:34][C:35]=3[N:36]=2)=[CH:11][C:10]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][C:21](=[O:28])[N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=2)=[CH:9][N:8]=1
Reactant: Nc1ncc(-c2cnn(CC(=O)N3CCCCC3)c2)cc1C=O
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3cc(-c4cnn(CC(=O)N5CCCCC5)c4)cnc3N)[nH]c2c1
Temperature: 25 °C

Procedure:
5.2 110.07 μl (0.558 mmol) of 38-40% sodium hydrogensulfite solution are added to a solution of 70 mg (0.223 mmol) of 2-amino-5-[1-(2-oxo-2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridine-3-carbaldehyde and 58.51 mg (0.268 mmol) of 6-(3,4-diaminophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one in 3 ml DMF, and the mixture is irradiated with microwaves for 30 min at 120° C. in the Biotage SmithSynthesizer. The reaction mixture is cooled to room temperature, and water is added. The precipitate is filtered off and washed with water and subsequently dried. The residue is purified by means of RP-HPLC: 6-(2-{2-amino-5-[1-(2-oxo-2-piperidin-1-ylethyl)-1H-pyrazol-4-yl]pyridin-3-yl}-3H-benzimidazol-5-yl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one as yellow solid; HPLC-MS [M+H]+ 512.2;
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:25]([O:29][C:30]([N:32]1[CH2:35][C:34]2([CH2:39][CH2:38][NH:37][CH2:36]2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:37]3[CH2:38][CH2:39][C:34]4([CH2:35][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])[CH2:33]4)[CH2:36]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CC(C)(C)OC(=O)N1CC2(CCNC2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)C2)C1
Temperature: -60 °C
Reaction time: 1 h
Yield: 42.9 %

Procedure:
(Z)-3-(3-(3,5-Bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.3 g, 1 eq.) dissolved in ethylacetate (20 mL) and cooled to −70° C. where tert-butyl-2,6-diazaspiro[3.4]octane-2-carboxylate (0.22 g, 1.2 eq.), T3P (50% in EtOAc) (0.61 mL, 1.2 eq.), followed by DIPEA (0.6 mL, 4 eq) were added. The clear reaction mixture was stirred at −60° C. for 1 h, concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product, which was purified by chromatography (3-4% Methanol in DCM) to yield (Z)-tert-butyl 6-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-2,6-diazaspiro[3.4]octane-2-carboxylate (0.2 g; 43% yield).