Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(OCC)(OCC)(OCC)=O.C([O-])(=O)C.[Na+].O.[Na+].[NH2:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH2:31][C:32]#[N:33])/[C:26]([O-:28])=[O:27])[N:24]=1>C(OCC)(=O)C.[Pd](Cl)Cl>[NH2:19][C:20]1[S:21][CH:22]=[C:23](/[C:25](=[N:29]/[O:30][CH2:31][C:32]#[N:33])/[C:26]([OH:28])=[O:27])[N:24]=1
Reactant: N#CCO/N=C(\C(=O)[O-])c1csc(N)n1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOP(=O)(OCC)OCC
Product: N#CCO/N=C(\C(=O)O)c1csc(N)n1
Reaction time: 0.17 h
Yield: 45.4 %

Procedure:
2.66 g (0.01 mol) of allyl 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic in 100 ml of ethyl acetate are treated while stirring with 17.73 mg (0.001 mol) of palladium chloride and 0.083 ml (0.0005 mol) of triethyl phosphate. After stirring for 10 minutes, 0.9 g (0.11 mol) of sodium acetate is added thereto. The reaction occurs after the addition of 1 ml of water and crude 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid sodium salt precipitates out. The mixture is stirred at room temperature for a further 24 hours, subsequently extracted twice with 30 ml of water each time, the aqueous solution is extracted once with ether and subsequently adjusted to pH 2 with 2N aqueous hydrochloric acid. After evaporation to dryness, the residue is dissolved in 50 ml of methanol, filtered and cooled. There are obtained 1.1 g (45.4%) of 2-(2-amino-4-thiazolyl)-2-[(Z)-(cyanomethoxy)imino]-acetic acid of melting point 140°-142° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:8]2=[O:20])=[C:4]([F:23])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:31][C:32]#[N:33]>C(#N)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:8](=[O:20])[CH:9]=[CH:10][C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:31][C:32]#[N:33])=[CH:15][CH:14]=3)=[CH:12]2)=[C:4]([F:23])[CH:3]=1
Reactant: O=c1ccc(-c2ccc(O)cc2)cn1Cc1ccc(Cl)cc1F
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCOc1ccc(-c2ccc(=O)n(Cc3ccc(Cl)cc3F)c2)cc1
Temperature: 180 °C
Yield: 42.1 %

Procedure:
According to Scheme 14 Method A: A suspension of 1-(4-chloro-2-fluorobenzyl)-5-(4-hydroxyphenyl)pyridin-2(1H)-one (1 eq, 1.21 mmol, 0.40 g), K2CO3 (10 eq, 12.1 mmol, 1.68 g) and 2-bromoacetonitrile (1 eq, 1.21 mmol, 0.15 g) in acetonitrile (10 mL) was heated in a microwave at 180° C. during 5 min. The reaction mixture was filtered, the filtrate was concentrated and the resulting crude residue was dissolved in CH2Cl2. The organic phase washed with water, dried over MgSO4, filtered and evaporated. The crude oil was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 25 g SiO2) using CH2Cl2/MeOH 98/2 as eluent followed by trituration in acetonitrile to afford 2-(4-(1-(4-chloro-2-fluorobenzyl)-6-oxo-1,6-dihydropyridin-3-yl)phenoxy)acetonitrile (0.51 mmol, 0.19 g, 42%) as a white solid.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C1COCC1.[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[CH:36]=[C:35]([O:37][CH:38]3[CH2:43][CH2:42][N:41]([C:44](N4C=CN=C4)=[O:45])[CH2:40][CH2:39]3)[N:34]=[CH:33][N:32]=1)[CH2:26][CH2:25]2)(=[O:21])=[O:20])[CH3:18]>O>[CH2:17]([S:19]([C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[N:27]([C:31]1[N:32]=[CH:33][N:34]=[C:35]([O:37][CH:38]3[CH2:39][CH2:40][N:41]([C:44]([O:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:45])[CH2:42][CH2:43]3)[CH:36]=1)[CH2:26][CH2:25]2)(=[O:20])=[O:21])[CH3:18]
Reactant: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)n3ccnc3)CC2)ncn1
Reactant: OC1CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)c1ccc2c(c1)CCN2c1cc(OC2CCN(C(=O)OC3CCC3)CC2)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
Cyclobutanol (90 μL, 1.15 mmol) and potassium tert-butoxide (50 mg, 0.446 mmol) were added to a THF (2.5 mL) suspension of the 5-(ethylsulfonyl)-1-(6-{[1-(1H-imidazol-1-ylcarbonyl)piperidin-4-yl]oxy}pyrimidin-4-yl)indoline (109 mg, 0.226 mmol) produced in Reference Example 31, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with ethyl acetate three times. The obtained organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [(i) hexane:ethyl acetate=50:50, V/V; (ii) ethyl acetate]. The obtained crude product was washed with diisopropyl ether to obtain the title compound as white powder (34.6 mg, yield: 32%).
Reaction SMILES: [NH:1]([C:3]1[S:7][N:6]=[C:5]([CH3:8])[CH:4]=1)[NH2:2].S(=O)(=O)(O)O.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH:23]([C:29](=O)[CH3:30])[CH2:24][C:25]([O:27][CH3:28])=[O:26])=O)=[CH:17][CH:16]=1.O>CO>[CH3:28][O:27][C:25](=[O:26])[CH2:24][C:23]1[C:29]([CH3:30])=[N:2][N:1]([C:3]2[S:7][N:6]=[C:5]([CH3:8])[CH:4]=2)[C:21]=1[C:18]1[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=1
Reactant: Cc1cc(NN)sn1
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC(=O)Cc1c(C)nn(-c2cc(C)ns2)c1-c1ccc(Cl)cc1

Procedure:
0.301 g (2.0 mmol) of 5-hydrazinyl-3-methylisothiazole and 0.099 ml (2.0 mmol) of concentrated sulfuric acid were added to 0.500 g (2.0 mmol) of methyl 3-[(4-chlorophenyl)carbonyl]-4-oxopentanoate in 10.00 ml of methanol, and the mixture was stirred under reflux for 6 hours. The mixture was poured into water and extracted with ethyl acetate.
Reaction SMILES: C(C1C=CC(CC(N)=O)=CC=1)C1C=CC=CC=1.[CH2:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH2:34])=O)[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([C:25]1[CH:26]=[C:27]([CH2:31][C:32]#[N:34])[CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NC(=O)Cc1cccc(Cc2ccccc2)c1
Agent: NC(=O)Cc1ccc(Cc2ccccc2)cc1
Product: N#CCc1cccc(Cc2ccccc2)c1

Procedure:
The two cyanomethyl intermediates, prepared above, were converted via the H202 conditions of Example 2 to their corresponding crystalline amides: 4-benzylphenylacetamide (93%), melting at 183-84° C. and 3-benzylphenylacetamide (59%), melting at 136-37° C.
Reaction SMILES: [I:1]Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11]>C(Cl)Cl>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([I:1])=[CH:6][C:5]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11]
Reactant: Nc1ccccc1C(=O)c1ccccc1Cl
Reactant: ClI
Solvent: ClCCl
Product: Nc1ccc(I)cc1C(=O)c1ccccc1Cl
Yield: 56 %

Procedure:
Iodine monochloride, 15 ml (21 g), was added to a solution of 23 g (0.1 mol) of (2-aminophenyl)(2 chlorophenyl)methanone [ref. E. Reeder and L. H. Sternbach, U.S. Pat. No. 3,371,085; February 1968] in 500 ml of methylene chloride cooled to -60° C. After stirring with cooling for 5 hours, the cooling bath was removed and the temperature of the reaction mixture was allowed to reach 0° C. Following the addition of 300 ml of aqueous sodium bisulfite solution, the two phase system was stirred for 10 minutes. The organic phase was separated, dried over sodium sulfate and evaporated. The residue was crystallized from ether/hexane to yield 20 g (56%) of (2-amino-5-iodophenyl) (2-chlorophenyl)methanone with m.p. 120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=O)[CH3:9])=[CH:4][C:3]=1[N+:13]([O-])=O>[Pd].O1CCOCC1>[NH2:13][C:3]1[C:2]([CH3:1])=[CH:12][C:11]2[C:8]([CH3:9])=[CH:7][O:6][C:5]=2[CH:4]=1
Reactant: CC(=O)COc1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1cc2c(C)coc2cc1N
Reaction time: 6 h

Procedure:
A mixture of 96.2 g (0.46 mole) of 1-(4-methyl-3-nitrophenoxy)-2-propanone, 10 g of 5% palladium on carbon and 960 ml of dioxane is hydrogenated for 6 hours at room temperature. The catalyst is subsequently filtered off and the filtrate is concentrated by evaporation in vacuo. The resulting residue is taken up in 2.5 liters of ethanol, 400 ml of concentrated hydrochloric acid are added and the whole is boiled under reflux for 30 hours. The ethanol is removed in vacuo and the residue is diluted with ice-water, rendered alkaline with 6N sodium hydroxide solution and extracted with ether. The crude product obtained after drying and concentration by evaporation of the organic phase is chromatographed over silica gel with methylene chloride/acetone. Recrystallisation of the pure fractions from petroleum ether yields 6-amino-3,5-dimethylbenzofuran having a melting point of 64°-65°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[O:10][CH:11]=1)(=O)=O.C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:26][CH:25]=1.[Li+].[Cl-]>O1CCOCC1.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>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:9]2[O:10][CH:11]=[C:7]([C:24]3[CH:25]=[CH:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:28][CH:29]=3)[N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc([Sn](C)(C)C)cc1
Reactant: COc1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)co2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1cccc(-c2nc(-c3ccc(NC(=O)OC(C)(C)C)cc3)co2)c1
Temperature: 100 °C
Yield: 73 %

Procedure:
In a sealable tube, 17 (436 mg, 1 eq), tert-butyl 4-(trimethylstannyl)phenylcarbamate (600 mg, 1.25 eq), LiCl (280 mg, 4 eq), Pd(PPh3)4 (77 mg, 5%) were mixed in 10 ml of dioxane. The tube was sealed and heated for 1 night at 100° C., cooled to RT, evaporated and purified by flash chromatography (SiO2, hexane/AcOEt, 85/15) giving 18 as a white solid in 73% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:51])=[C:8]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:29]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:30]=4[C:31]([CH3:48])=[CH:32][N:33]5S(C4C=CC(C)=CC=4)(=O)=O)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][C@H:19]4[CH3:28])[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2].[OH-].[NH4+].[OH-].[K+]>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:51])=[C:8]([N:10]2[CH2:50][CH2:49][C:13]3[N:14]=[C:15]([C:29]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:30]=4[C:31]([CH3:48])=[CH:32][NH:33]5)[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH2:20][C@H:19]4[CH3:28])[C:12]=3[CH2:11]2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(CC(N)=O)C[C@H]6C)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3cccc4[nH]cc(C)c34)nc(N3CCN(CC(N)=O)C[C@H]3C)c2C1
Temperature: 100 °C

Procedure:
A mixture of (R)-2-(4-(6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-3-methylpiperazin-1-yl)acetamide (0.075 mg, 0.106 mmol), 30% ammonium hydroxide (0.63 mL 15.94 mmol) and potassium hydroxide (0.054 g, 0.956 mmol) in ethanol (3 mL) was heated in a microwave reactor at 100° C. for 1 h. The reaction mixture was concentrated and then filtered before being purified via HPLC (RP C18, 15-85% CH3CN in H2O with 0.1% NH4OH to provide the title compound. 1H NMR (400 MHz, CD3CN) δ ppm 9.16 (br. s., 1 H) 7.45 (d, J=8.08 Hz, 1H) 7.25 (dd, J=7.20, 1.14 Hz, 1 H) 7.15 (dd, J=15.28, 7.71 Hz, 2 H) 7.01-7.09 (m, 2 H) 6.82-6.94 (m, 2 H) 5.80 (br. s., 1 H) 3.94-4.13 (m, 3 H) 3.51-3.60 (m, 1 H) 3.41-3.50 (m, 1 H) 3.28-3.41 (m, 2 H) 2.95-3.12 (m, 2 H) 2.82-2.95 (m, 3 H) 2.78 (d, J=10.86 Hz, 1 H) 2.57-2.66 (m, 1 H) 2.47-2.56 (m, 1 H) 2.37 (td, J=10.74, 3.03 Hz, 1 H) 2.26 (s, 3 H) 2.05 (s, 3 H) 1.30 (d, J=6.82 Hz, 3 H) 1.23 (dd, J=6.82, 1.01 Hz, 6 H); MS (ESI+) m/z 552.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[C:7]([F:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][S:14](Cl)(=[O:16])=[O:15].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][S:14]([O:11][CH2:10][C:8]1[CH:9]=[C:2]([F:1])[C:3]([C:4]#[N:5])=[CH:6][C:7]=1[F:12])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(F)c(CO)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(F)c(C#N)cc1F
Temperature: 0 °C

Procedure:
To an ice cooled solution of 2,5-difluoro-4-hydroxymethylbenzonitrile (3.10 g, 0.0183 mol; see step (iii) above) and methanesulfonyl chloride (2.21 g, 0.0192 mol) in 60 mL of methylene chloride was added triethyl amine (1.95 g, 0.0192 mol) with stirring. After 1.5 h at 0° C. the mixture was washed with water, dried (Na2SO4) and evaporated. The product could be used without further purification. Yield: 4.5 g (99%).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[N:5]=1)[CH3:3].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:5]2[C:6]3[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])=[CH:17][CH:18]=1
Reactant: CC(C)c1nc2c([nH]1)CCCC2=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a stirred suspension of Intermediate 56 (867 mg), 1-(bromomethyl)-4-chlorobenzene (1100 mg) and tetrabutylammonium bromide (784 mg) in toluene (20 mL) at ambient temperature was added aqueous sodium hydroxide 20% wt (9 mL). The reaction was stirred at ambient temperature for 2 hr. The reaction was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and evaporated in vacuo to give the required product (0.89 g). LC/MS MH+ 303, Rt 2.02 min (5 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.C([N:15]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:15])=[O:11])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CC#N
Product: NC(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 87.5 %

Procedure:
4-Fluorophenylacetic acid (1 g, 6.49 mmol) was dissolved in acetonitrile (40 ml) and cooled to 0° C. in an ice bath. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.492 g, 7.79 mmol) was added, followed by 1-hydroxybenzotriazole (1.19 g, 7.79 mmol). The mixture was stirred at 0° C. for 2.5 hours, and then concentrated ammonium hydroxide (0.865 ml, 13.0 mmol) was added slowly. The mixture then stirred at RT for an additional 2 hours. After this time the solids were filtered off, and the filtrate was diluted with ethyl acetate (50 mL). The solution was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried (MgSO4) and concentrated in vacuo to yield 2-(4-fluorophenyl)acetamide (0.87 g, 88% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (broad s, 1H), 7.26 (m, 2H), 7.09 (m, 2H), 6.87 (broad s, 1H), 3.34 (s, H).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:17]2[N:18]=[CH:19][S:20][C:16]=2[CH:15]=[CH:14][CH:13]=1)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[CH:5]1[C:4]2[C:13]3[C:12](=[C:17]4[C:16](=[CH:15][CH:14]=3)[S:20][CH:19]=[N:18]4)[NH:11][S:8](=[O:10])(=[O:9])[C:3]=2[CH:2]=[CH:7][CH:6]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2scnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(ccc3scnc23)-c2ccccc21
Yield: 19.6 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-benzothiazol-4-yl-benzenesulfonamide (Intermediate 289) (190 mg, 0.62 mmol), t-butyl nitrite (96 mg, 0.93 mmol), AcOH (1.9 ml) and THF (4 ml) gave the title compound (35 mg, 19.5%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].Cl[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH3:14])=[O:9]>>[OH:4][CH2:3][CH:2]([NH:1][C:8](=[O:9])[O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5][OH:6]
Reactant: CCCCOC(=O)Cl
Reactant: NC(CO)CO
Product: CCCCOC(=O)NC(CO)CO

Procedure:
The general procedure described in Example 2 was followed using serinol and n-butyl chloroformate to prepare nBuDHPC.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](B(O)O)=[CH:3]1.Cl[C:20]1[C:25]([CH:26]=[O:27])=[C:24]([N:28]2[CH2:41][CH2:40][N:31]3[C:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=4[C:38]([F:39])=[C:30]3[C:29]2=[O:42])[N:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>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].O>[F:39][C:38]1[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[N:31]2[CH2:40][CH2:41][N:28]([C:24]3[N:23]=[CH:22][CH:21]=[C:20]([C:4]4[N:5]=[C:6]([NH:9][C:10]5[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=5)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=4)[C:25]=3[CH:26]=[O:27])[C:29](=[O:42])[C:30]=12
Reactant: Cn1cc(B(O)O)nc(Nc2cccnc2)c1=O
Reactant: O=Cc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)nc(Nc2cccnc2)c1=O
Temperature: 50 °C
Yield: 49.4 %

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 186b (127 mg, 0.52 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (180 mg, 0.52 mmol), Na2CO3 (110 mg, 1.04 mmol), PdCl2(dppf) (38 mg, 0.052 mmol), DMF (12 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 8 hours under nitrogen. The reaction was then cooled to room temperature and concentrated under reduce pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 methylene chloride/methanol to afford 186c (132 mg, 49%) as a brown solid. MS-ESI: [M+H]+ 514.3.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:20]([Cl:21])=[C:19]([O:22][CH3:23])[CH:18]=[CH:17][C:5]=1[C:6](=[N:15][OH:16])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[F:14]>CN(C=O)C>[Cl:21][C:20]1[C:4]2[O:16][N:15]=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=3[F:14])[C:5]=2[CH:17]=[CH:18][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(C(=NO)c2ccc(Cl)cc2F)c(Cl)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(-c3ccc(Cl)cc3F)noc2c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2.24 g of NaH in 100 ml DMF, 21.75 g of 2,3-dichloro-4-methoxy-4'-chloro-2'-fluorobenzophenone oxime in 100 ml of DMF is added dropwise. After addition the mixture is stirred one hour and the reaction mixture poured into ice water. A product which precipitates is filtered and dried giving a mixture of isomers which is chromatographed on silica gel with 50% hexane and 50% toluene as eluant to yield 7-chloro-3-(4-chloro-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 193°-194° C.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH3:12])[N:10]([CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)/[C:9](=[N:19]/C(=O)C(F)(F)F)/[CH:8]=1)([CH3:6])([CH3:5])[CH3:4]>O.CO>[C:3]([C:7]1[N:11]([CH3:12])[N:10]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:9](=[NH:19])[CH:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)C(F)(F)F)n1CC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1c(C(C)(C)C)cc(=N)n1CC1CCCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A solution of sodium hydroxide (1.7 g, 41.5 mmol) in water (2 mL) was added to a solution of Example 127D (2.75 g, 8.3 mmol) in MeOH (10 mL) and the mixture stirred at 50° C. for 3 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined organic extracts were concentrated and the residue crystallized from MeOH and EtOAc to afford the title compound (1.9 g, 8.1 mmol, 97% yield). 1H NMR (300 MHz, Methanol-d4) δ ppm 1.23-1.37 (m, 2H), 1.41 (s, 9H), 1.53-1.64 (m, 2H), 1.64-1.78 (m, 4H), 2.17-2.44 (m, 1H), 3.34 (s, 1H), 3.80 (s, 3H), 4.12 (d, J=7.5 Hz, 2H), 5.75 (s, 1H); MS (ESI+) m/z 236 [M+H]+.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[C:14]2[N+:20]([O-:22])=[O:21])=[O:10])=S)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl>C1(C)C=CC=CC=1>[CH:1]([NH:4][C:5]1[O:10][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[N+:20]([O-:22])=[O:21])=[N:8][N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)NC(=S)NNC(=O)c1ccc2[nH]cc([N+](=O)[O-])c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc([N+](=O)[O-])c3c2)o1
Yield: 89.4 %

Procedure:
To a suspension of N-isopropyl-2-(3-nitro-1H-indole-5-carbonyl)hydrazinecarbothioamide (1.5 g, 4.672 mmol) in toluene (15 mL) was added EDC HCl (1.3 g, 7.009 mmol) in one lot and the reaction was heated to reflux for 16 h. After completion, toluene was removed in vacuo and the residue was treated with water (25 mL) to get a precipitate. The precipitate was filtered washed and dried. The crude product was washed with 10% EtOAc in petroleum ether to afford N-isopropyl-5-(3-nitro-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (1.2 g, 92%) as pale yellow colored solid. MS (ESI, pos. ion) m/z: 288.1 (M+1); 1H-NMR (300 MHz, DMSO-d6): δ 12.88 (brs, 1H), 8.75 (s, 1H), 8.47 (s, 1H), 7.67-7.84 (m, 3H), 3.69-3.76 (m, 1H), 1.21 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]([N-:9][CH:10]=[CH:11][N-:12][C:13]([CH3:20])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[Li+].[Li+].[Cl:23][SiH:24](Cl)Cl>CCCCCC>[Cl:23][SiH:24]1[N:9]([C:2]([CH3:1])([CH3:8])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7])[CH:10]=[CH:11][N:12]1[C:13]([CH3:20])([CH3:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: Cl[SiH](Cl)Cl
Reactant: CC(C)(C)CC(C)(C)[N-]C=C[N-]C(C)(C)CC(C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Product: CC(C)(C)CC(C)(C)N1C=CN(C(C)(C)CC(C)(C)C)[SiH]1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
In an argon atmosphere, a dilithium(N,N′-bis(1,1,3,3-tetramethylbutyl)-1,2-vinylenediaminide) solution prepared according to the procedure and reagent quantities described in Reference Example-11 was added to a hexane (150 mL) solution containing 25.00 g (184.6 mmol) of trichlorosilane, and the mixture was stirred at room temperature for 3 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 125° C./85 Pa) to obtain 2-chloro-1,3-bis(1,1,3,3-tetramethylbutyl)-1,3-diaza-2-silacyclopent-4-ene (Si(tOctNCHCHNtOct)(H)Cl) as a pale yellow liquid (yielded amount: 57.22 g, yield: 90%).