Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]#[C:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13][C:14](=[O:16])[CH3:15].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[O:13][C:14](=[O:16])[CH3:15]
Reactant: [H][H]
Reactant: COCCC#Cc1ccncc1OC(C)=O
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: COCCCCc1ccncc1OC(C)=O

Procedure:
To a degassed solution of 9.9 mmol acetic acid 4-(4-methoxy-but-1-ynyl)-pyridin-3-yl ester and 0.51 mmol quinoline in 230 ml ethyl acetate is added 0.56 mmol 10% Pd/C. The suspension is vigorously stirred under an atmospheric pressure of hydrogen for 2 hours. The catalyst is removed by filtration and the solvent is evaporated. The title compound is obtained from the residue by means of flash chromatography (SiO2 60 F) and identified based on its Rf value.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:30][CH:29]=2)[C:17]([O:19]C)=[O:18])=[O:13])[CH2:6]1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO>[C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:30][CH:29]=2)[C:17]([OH:19])=[O:18])=[O:13])[CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCCCc2ccc(OCCCCOc3ccccc3)cc2)c(C(=O)NC2CCCC(C(=O)O)C2)c1
Temperature: 60 °C
Yield: 96.7 %

Procedure:
A solution of 638 mg of methyl 3-({[3-(methoxycarbonyl)cyclohexyl]-amino}carbonyl)-4-{3-[4-(4-phenoxybutoxy)phenyl]propoxy}benzoate (racemate B) in 4 ml of tetrahydrofuran (THF) and 4 ml of methanol is mixed with 4 ml of 2 molar sodium hydroxide solution and heated at 60° C. for one hour. The pH is then adjusted to a value of 3-4 with 2 molar hydrochloric acid, and the mixture is extracted with ethyl acetate. The organic extract is washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. Filtration and evaporation result in a crude product which is purified by recrystallization from diethyl ether. 589 mg of product are isolated.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13](CCl)=[CH:12][N:11]=1.[CH3:18]N(C=O)C.C([O-])([O-])=O.[K+].[K+]>O>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH:4]2[CH2:5][C:6](=[O:7])[N:2]([O:1][CH3:18])[C:3]2=[O:8])=[CH:12][N:11]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1CCC(=O)N1O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CON1C(=O)CC(c2ccc(Cl)nc2)C1=O
Temperature: 15.5 °C
Reaction time: 0.08 h
Yield: 49 %

Procedure:
To a 5 L-three neck flask equipped with a mechanic stirrer, heating mantle with temperature controller and a gas outlet, were charged N-hydroxysuccinimide (426 g, 3.7 mol), 2-chloro-5-chloromethylpyridine (500 g, 3.1 mol) and anhydrous DMF (1 L). The mixture was stirred for 5 min when inner temperature dropped to 8.5° C. Anhydrous K2CO3 (640 g, 4.6 mol) was charged in one portion followed by anhydrous DMF (0.5 L). It was stirred for 5 min when inner temperature raised to 15.5° C. The mixture was heated to 70° C. (preset) within 30 min but the temperature continued to rise to 89° C. over 1 h of reaction period, during which a lot of gas was evolved and the reaction was finished as judged by MS and TLC, or simply the termination of gas-evolving. It was cooled down to room temperature, poured into water (6 L) with mechanic stirring. The insoluble was collected by filtration and washed with water (1.5 L), air-dried for 60 h to give the desired product as an off-white powder (364 g, 49%). ESIMS m/e (M+H)+: 241. 1H NMR (500 MHz, CDCl3): 8.44 (s, 1H), 7.95 (d, 1H, 3J=8.5 Hz), 7.41 (d, 1H, 3J=8.0 Hz), 5.14 (s, 2H), 2.73 (s, 4H) ppm. 13C NMR (125 MHz, CDCl3): δ 170.8, 152.6, 150.2, 140.2, 128.2, 124.4, 74.9, 25.4.
Reaction SMILES: O1[CH2:6][CH2:5][O:4][CH2:3]C1.Cl[C:8]1[N:13]=[C:12]([NH:14][CH3:15])[N:11]=[C:10]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:23])[CH2:18][CH2:17]2)[N:9]=1.[CH3:36][C:37]1C=CC=[CH:39][C:38]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)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.O.CC#N>[CH3:15][NH:14][C:12]1[N:13]=[C:8]([C:37]2[CH:36]=[CH:6][C:5]([O:4][CH3:3])=[CH:39][CH:38]=2)[N:9]=[C:10]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:33])([F:35])[F:34])=[O:23])[CH2:20][CH2:21]2)[N:11]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CNc1nc(Cl)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Reactant: C1COCCO1
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: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CNc1nc(-c2ccc(OC)cc2)nc(N2CCC(C(=O)NCc3ccccc3C(F)(F)F)CC2)n1
Temperature: 150 °C

Procedure:
In a microwave vial, to a 1,4-dioxane (3.0 ml) suspension of 1-[4-chloro-6-(methylamino)-1,3,5-triazin-2-yl]-N-{[2-(trifluoromethyl)phenyl]methyl}-4-piperidine carboxamide (Intermediate 7d, 75 mg, 0.17 mmol, 1.0 equiv) was added (2-methylphenyl)boronic acid (29 mg, 0.21 mmol, 1.2 equiv), Na2CO3 (37 mg, 0.35 mmol, 2.0 equiv) in 3:1 CH3CN:H2O, and lastly Pd(PPh3)4 (10 mg, 0.0088 mmol, 0.05 equiv). The reaction mixture was heated at 150° C. for 25 minutes. The resulting suspension was diluted with ethyl acetate (10 ml), washed with water (5 ml), dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in 2.0 ml DMSO and purified via reverse-phase HPLC purification to afford the title compound. MS (ES+): m/e 501.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1F>>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[O:9][CH:6]1[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]2[O:12][CH:11]=[CH:10][C:5]1=2
Reactant: CN1CCC(O)c2ccoc2C1
Reactant: Fc1c(Cl)cccc1Cl
Product: CN1CCC(Oc2c(Cl)cccc2Cl)c2ccoc2C1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2,6-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:10])[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Na]>C(O)CCC>[CH2:16]([C:2]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[C:1]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: CCCCOC(=O)CC(=O)OCCCC
Agent: [Na]
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCCC)(C(=O)OCCCC)C(=O)OCCCC

Procedure:
62 m mol of dibutyl malonate, 63 m mol of stearyl bromide, and 69 m mol of sodium were made to react in butanol in the presence of 2 m mol of a crown ether, thereby forming 30 m mol of dibutyl distearylmalonate. Dibutyl distearylmalonate, 15 m mol, was first hydrolyzed, and was then heated in vacuum to be decarboxylated, whereby obtaining 10 m mol of 2-octadecyl eicosanoic acid. This acid, 8 m mol, was converted into its acid chloride. The acid chloride was allowed to react with 10 m mol of p-amino-methlylsulfonylanilide in pyridine, thereby obtaining 7 m mol of p-methylsulfonamide-3-heptadecyleicosanoylanilide. The eicosanoylanilide, 5 m mol, was allowed to react with lead tetraacetate in toluene, thus forming 3.2 m mol of N-(2-octadecyleicosanoyl)-N'methylsulfonyl-p-quinonediimine which is represented by the following formula: ##STR29##
Reaction SMILES: C(N[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=[CH:12][N:11]=1)CC1C=CC=CC=1.ClC1N=CN=C(N2CCCN3C(=O)C=C(C4C=CC=CC=4)C=C23)C=1.[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64][CH2:65][NH2:66]>>[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[CH2:64][CH2:65][NH:66][C:12]1[N:11]=[CH:10][N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][N:18]3[C:22](=[O:32])[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:25]=[C:17]23)[CH:13]=1
Reactant: NCCc1ccccc1Cl
Reactant: O=c1cc(-c2ccccc2)cc2n1CCCN2c1ccnc(NCCc2ccccc2)n1
Agent: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(Cl)ncn1
Product: O=c1cc(-c2ccccc2)cc2n1CCCN2c1cc(NCCc2ccccc2Cl)ncn1

Procedure:
Followed the same procedure described for the synthesis of 1-(2-phenethylamino-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one, 1-(6-chloro-pyrimidin-4-yl)-8-phenyl-1,2,3,4-tetrahydro -pyrido[1,2-a]pyrimidin-6-one (0.136 g, 0.40 mmol) was reacted with 2-(2-chlorophenyl)ethylamine (0.17 mL, 1.2 mmol) to give the title compound as a yellow solid. MS m/e 458 (M+H)+.
Reaction SMILES: N1CCCCC1.C=O.[CH3:9][CH:10]([CH3:27])[CH2:11][C@@H:12]([C:24]([OH:26])=[O:25])[CH:13]([C:21](O)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)(C)C>[C:17]([O:16][C:14]([C:13]([C@@H:12]([CH2:11][CH:10]([CH3:27])[CH3:9])[C:24]([OH:26])=[O:25])=[CH2:21])=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)C[C@@H](C(=O)O)C(C(=O)O)C(=O)OC(C)(C)C
Agent: C=O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: C=C(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)O
Reaction time: 8 h
Yield: 74.3 %

Procedure:
7.8 ml of piperidine and 20 ml of a 40% aqueous formaldehyde solution were added to a solution of 6.0 g of 1-tert.butyl dihydrogen 4-methyl-1(RS),1,2(R)-pentanetricarboxylate in 80 ml of isopropyl alcohol and the mixture was stirred overnight under a nitrogen atmosphere. The solvent was evaporated and the residue was dissolved in ethyl acetate. The ethyl acetate phase was washed in succession with 1M aqueous hydrochloric acid, warm water and brine and the dried over anhydrous magnesium sulphate. The solvent was evaporated to give 3.94 g of 2(R)-[1-(tertbutoxycarbonyl)vinyl]-4-methylvaleric acid in the form of a clear oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[N:3]=[CH:2]1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O.C1[CH2:27][O:26][CH2:25][CH2:24]1>CCOCC>[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18][O:10][C:9]1[C:4]2[N:3]=[CH:2][N:1]([CH2:27][O:26][CH2:25][CH2:24][Si:14]([CH3:20])([CH3:15])[CH3:13])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Oc1cccc2[nH]cnc12
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(C)CCOCOc1cccc2c1ncn2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of 1H-benzoimidazol-4-ol (440 mg, 3.28 mmol) in THF (13 mL) at room temperature was added NaH (60% dispersion in mineral oil; 276 mg, 6.89 mmol) in 3 portions over 15 min. The mixture was stirred at room temperature for 1.5 hours before it was heated to 65° C. for 30 min. The THF was removed and replaced with DMF (10 mL) and the mixture was warmed to 65° C. for 30 min. The mixture was cooled to 10° C., 2-(trimethylsilyl)ethoxymethyl chloride (1.19 mL, 6.72 mmol) was added dropwise and the mixture was stirred at room temperature overnight. H2O and Et2O were added, the mixture was filtered and the phases separated. The aqueous phase was extracted into Et2O (×3), dried (MgSO4) and concentrated in vacuo. The product was purified by SiO2 chromatography and followed by trituration with Et2O to provide the title compound (177 mg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].[I-].[K+].CN(C=O)C>C(OCC)(=O)C.O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 84.8 %

Procedure:
Chloroacetaldehyde diethyl acetal (2.00 g), potassium benzoate (1.91 g), potassium iodide (0.41 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration, the organic layer was separated, was subjected to vacuum concentration and then to Kugelrohr distillation at 110-120° C. and at 1 mmHg and thereby yielded the target compound (2.41 g) in a yield of 77%.
Reaction SMILES: CN(C)C=O.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH2:17]([O:22][CH3:23])[CH2:18][CH2:19][C:20]#[CH:21]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[CH3:23][O:22][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: C#CCCCOC
Reactant: NS(=O)(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 22 h

Procedure:
135 ml of N,N-dimethylformamide and 22 ml of triethylamine are taken and 7.5 g of 2-iodobenzenesulfonamide, 2.6 g of pent-4-yn-1-yl-methyl ether as well as 0.067 g of copper(I) iodide and 0.144 g of bis(triphenylphosphine)palladium(II) dichloride are added. The reaction mixture is heated to 65° and stirred for 22 hours at that temperature under argon. After that time, the N,N-dimethylformamide is distilled off at 0.1 torr and 40°. The crude product is purified on 500 g of silica gel (Merck Si 60, 40-63 μm) with hexane/ethyl acetate=2/1 as eluant. The fractions containing the product are concentrated by evaporation at 15 torr and 40° to yield white crystalline 2-(5-methoxy-pent-1-yn-1-yl)-benzenesulfonamide, melting point: 59°-61°.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24](C=O)=[CH:23][C:22]=1[CH3:29].[C:31](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:18][O:19][C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:14]([N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:8][C:9]=2[CH3:15])[CH3:31])=[C:23]([CH3:24])[C:22]=1[CH3:29]
Reactant: CC(=O)O
Reactant: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1C
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)c1ccc(N(C)c2ccc(O[Si](C)(C)C(C)(C)C)cc2C)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.1 %

Procedure:
To a solution of [4-(tert-butyl-dimethyl-silanyloxy)-2-methyl-phenyl]-methyl-amine (0.64 g, 2.6 mmol) and 4-formyl-2-methyl-benzoic acid methyl ester (0.38 g, 2.1 mmol), acetic acid (0.25 g, 4.2 mmol) in 1,2-dichloroethane (10.0 mL) is added sodium triacetoxyborohydride (0.89 g, 4.2 mmol) in portions. The mixture is stirred at room temperature overnight. The reaction is quenched with 5% aq. sodium bicarbonate (5 mL) and is partitioned between EtOAc (60 mL) and water (50 mL). The organic layer is washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated. The residue is purified by flash column chromatography to afford the title compound as a syrup (1.0 g, 95%). LC-ES/MS m/e 414.3 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25].O>CC(N(C)C)=O>[S:24]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:13]2)[C:3]=1[C:4]#[N:5])(=[O:27])(=[O:26])[NH2:25]
Reactant: CC(C)CC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Reactant: NS(=O)(=O)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a stirred solution of (S)-2-amino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile (example 5b, 54.55 g, 172.95 mmol) in DMA (110 mL) cooled to 0° C. in an ice bath was added sulfamoyl chloride (55 g, 476 mmol) in two portions (20 g and 35 g). The reaction mixture was stirred for 30 minutes at 0° C. under N2, then at room temperature for 4 hours. The reaction mixture was poured slowly into rapidly stirred cold water (2 L) to provide a milky solution. An additional 800 mL of water was added in several portions to precipitate the desired product (at this point the milky solution has become clear). The precipitate was collected by decantation of the water and was suspended in ethyl acetate (500 mL) then rapidly stirred until it became a fine white solid. The solid material was collected by vacuum filtration and dried under vacuum to give (S)-2-sulfamoylamino-6-((1-(3-methylbutanoyl)piperidin-3-yl)methoxy)benzonitrile as a white solid (59.25 g, 150.2 mmol) in 87% yield. MS 395 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4N(CC(F)(F)F)N=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=CC2C3N=C(C(N)=O)SC=3CCOC=2C=1.[NH:44]([CH2:46][CH:47]([OH:49])[CH3:48])[NH2:45]>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:44]([CH2:46][CH:47]([OH:49])[CH3:48])[N:45]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(O)CNN
Agent: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: CC(O)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with 1-hydrazino-propan-2-ol to give 1-[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-[1,2,4]triazol-1-yl]-propan-2-ol. MS(ESI+) 407.0/409.0.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C1C[O:36]CC1>>[C:11]([O:15][C:16]([NH:18][CH2:22][CH2:21][CH:20]([CH2:24][C:25]1[CH:32]=[CH:31][C:28]([CH3:29])=[CH:27][CH:26]=1)[C:19]([OH:23])=[O:36])=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCOC1
Reactant: Cc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: Cc1ccc(CC(CCNC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 49 %

Procedure:
To a solution containing LiHMDS (1.0M, 11.3 mL, 11 mmol) in 40 mL of THF under a nitrogen atmosphere at −78C was added a solution of 2-Oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (2.gg, 11 mmol) in 15 mL of THF dropwise over 5 minutes. After complete addition, the reaction was allowed to stir at −78° C. for 45 minutes, followed by the addition of a solution containing 4-methyl benzyl bromide (2.1 g, 11 mmol) in 15 mL of THF dropwise over 5 minutes. The reaction was allowed to stir at −78C for 1 hour then warmed to 0 C and stirred for 1 hour. The mixture was quenched with 36 mL of 3M LiOH and allowed to stir at room temperature overnight. The reaction was diluted with water and washed with ether. The aqueous phase was acidified with 1N HCl and extracted with DCM. The organic phase was dried over magnesium sulfate. Filtration and removal of solvent gave 4-tert-Butoxycarbonylamino-2-(4-methylbenzyl)-butyric acid (1.61 g, 49%.) LCMS (APCI−) m/z 306 [M-Boc-H]−; Rt: 2.14 min.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:18]=1.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([C:17]3[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[N:18]=3)[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CN(c3nc(-c4ccncn4)cc(=O)n3C)CCO2)cc1
Yield: 90.4 %

Procedure:
A solution of (S)-2-(4-methoxyphenyl)morpholine hydrochloride (0.30 g, 1.35 mmol), 2-chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (0.40 g, 1.75 mmol) and triethylamine (0.56 ml, 4.05 mmol) in tetrahydrofuran(6 ml) was refluxed for several hours. The reaction mixture was removed in vacuo. The residue was dissolved in 1N hydrochloric acid and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with ethyl acetate as the eluent to give the title compound (463 mg, 90%)
Reaction SMILES: [CH2:1]([C:8]1=[N:9][NH:10][C:11](=[O:24])/[C:12]/1=[C:13]1\[NH:14][C:15]2[C:20]([C:21](Cl)=[CH:22]\1)=[CH:19][CH:18]=[CH:17][CH:16]=2)C1C=CC=CC=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([SH:32])=[CH:28][CH:27]=1>>[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14]/[C:13](=[C:12]3/[C:8]([CH3:1])=[N:9][NH:10][C:11]/3=[O:24])/[CH:22]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(S)cc1
Reactant: O=C1NN=C(Cc2ccccc2)/C1=C1\C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-3-benzyl-4-(4-chloroquinolin-2(1H)-ylidene)-1H-pyrazol-5(4H)-one and 4-aminothiophenol under conditions similar to those described in Example 6. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.81 (s, 2H) 6.77-6.79 (m, 3H) 7.23-7.30 (m, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.40-7.48 (m, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H); ESI-MS: m/z calc'd for C25H20N4OS 424.14. found 424.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH3:21])[CH:11]=1)=[O:9])(C)([CH3:3])[CH3:2].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(O)(C(F)(F)F)=O.CC(C)=O>[CH3:2][C:1]1([CH3:3])[O:5][C:6](=[O:22])[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N:16]3[CH:20]=[CH:19][N:18]=[C:17]3[CH3:21])[CH:11]=2)[O:9]1
Reactant: Cc1nccn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: Cc1nccn1-c1cccc(C2=CC(=O)OC(C)(C)O2)c1

Procedure:
Prepared from 3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H8) by stirring in TFA/acetone with TFAA according to general procedure J (method b). Obtained as a beige solid (2.13 g).