Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC(NN=CC)=CC=1N[S:13]([CH3:16])(=[O:15])=[O:14].ClC1C=CC([N+]([O-])=O)=CC=1N.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][C:30]=1[N:38]([S:13]([CH3:16])(=[O:15])=[O:14])[S:39]([CH3:42])(=[O:40])=[O:41]
Reactant: CC=NNc1ccc(Cl)c(NS(C)(=O)=O)c1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1Cl
Agent: CS(=O)(=O)Cl
Agent: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc([N+](=O)[O-])ccc1Cl)S(C)(=O)=O
Temperature: 0 °C

Procedure:
To prepare the starting material, acetaldehyde 4-chloro-3-methylsulfonylaminophenylhydrazone, a mixture of 20.0 5 (116 mmoles) of 2-chloro-5-nitroaniline (compound 4, FIG. 1), 24.6 g (243 mmoles) of triethylamine and 100 ml of methylene chloride was cooled in an ice bath, and a solution of 27.8 g (243 mmols) of methylsulfonyl chloride in 20 ml of methylene chloride was added dropwise. When the addition was about half complete the ice bath was removed. After completion of the addition, the mixture was allowed to stand for an hour and then filtered to remove undesired salts. The filtrate was evaporated under reduced pressure to give a yellow solid which was washed with 100 ml of water; the filter cake was then mixed with 100 ml of ethanol and then filtered rapidly, and the resulting off-white solid was dried in vacuo to give 32.7 g of 2-chloro-5-nitro-1-bis(methylsulfonyl)amino-benzene. The latter was then mixed with 50 ml of ethanol; 8 g of NaOH in 20 ml of water was added slowly with stirring, after which the mixture was diluted with 300 ml of water followed by the addition of 45 ml of 6N HCl, yielding a precipitate which was collected by filtration and dried in vacuo to give 24.3 g of 2-chloro-5-nitro-1-methylsulfonylaminobenzene (compound 4, FIG. 1). The latter material was reduced with iron powder to form 17.7 g of 4-chloro-3-methylsulfonylaminoiline.
Reaction SMILES: Br[C:2]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].[OH:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[CH2:11]([C:2]1([CH:23]2[CH2:24][NH:25][CH2:26][CH2:27][N:22]2[CH2:21][CH2:20][OH:19])[C:7](=[O:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O
Reactant: OCCN1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCC1(C2CNCCN2CCO)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-Bromo-5-octylbarbituric Acid (23.52 g) in 70 ml of dimethylsulfoxide, kept under nitrogen atmosphere and at a temperature of 5-10° C., is dropped N-(2-hydroxyethyl)piperazine (36.2 ml), then the mixture is stirred at room temperature for 2 hours 30 minutes. The reaction mixture is poured into water (1 l) under stirring and cooling with an ice bath. The white solid which separates is recovered by filtration, washed with water and dried under vacuum at 40° C. to give, after crystallization from ethanol (140 ml) 10.91 g of the product as a white solid, m.p. 183-184° C.
Reaction SMILES: Br[CH:2]1[C:11](=O)[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH2:35])=[S:34])=[CH:28][C:27]=2[O:36][CH3:37])[CH:25]=1>C(O)C.CCOC(C)=O>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33]3[S:34][C:2]4[CH2:3][C:4]5([O:8][CH2:7][CH2:6][O:5]5)[CH2:9][CH:10]([C:13]5[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=5)[C:11]=4[N:35]=3)=[CH:28][C:27]=2[O:36][CH3:37])[CH:25]=1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Reactant: O=C1C(Br)CC2(CC1c1ccc(F)cc1)OCCO2
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(Nc2nc3c(s2)CC2(CC3c3ccc(F)cc3)OCCO2)ccc1-n1cnc(Cl)c1
Yield: 57 %

Procedure:
A mixture of 7-bromo-9-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-on (50 mg, 0.177 mmol, preparation AAC) and 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (91 mg, 0.276 mmol, from step 4 of preparation A) was heated in ethanol (0.25 mL) at 80° C. for 45 min. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (50% acetone/hexanes) to give 54 mg (57% yield) of the titled compound as a white solid. LC-MS (M+H)+ 513.2. 1H NMR (400 MHz, chloroform-d) δ ppm 7.49 (dd, J=11.21, 1.89 Hz, 2 H) 7.15-7.24 (m, 2 H) 7.08 (d, J=8.31 Hz, 1 H) 6.93-7.04 (m, 3 H) 6.58 (dd, J=8.56, 2.27 Hz, 1 H) 4.16-4.33 (m, 1H) 3.89-4.15 (m, 4H) 3.49 (s, 3 H) 3.13 (dd, J=16.37, 3.02 Hz, 1 H) 2.82-2.98 (m, 1H) 1.98-2.32 (m, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][C:3]=1[CH3:16].O.Cl>O1CCCC1>[Br:1][C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[CH2:8][OH:9])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(OC(C)(C)C(=O)O)cc(C)c1Br
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC(C)(C)CO)cc(C)c1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2-(4-Bromo-3,5-dimethyl-phenoxy)-2-methyl-propionic acid (4.45 g) is dissolved in 50 mL of tetrahydrofurane, borane methylsulfide complex (2.6 mL) is added and the reaction mixture is stirred at room temperature for 5 h. The reaction mixture is cooled to 0° C., 10% HCl water solution is added dropwise and the reaction mixture is extracted with dichloromethane. The organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The residue is chromatographed on silica gel (hexane/ethyl acetate 100:0→50:50) to give the title compound. Yield: 2.6 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][N:8]=1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]1[N:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.4 %

Procedure:
A solution of methyl 6-((3,4-dichlorobenzyl)amino)nicotinate (0.88 g, 2.83 mmol) in THF (18.9 mL) was cooled to −78° C. and a 1M solution of DIBAL-H (14.14 mL, 14.14 mmol) in toluene was added. The mixture was stirred for 1.5 h while warming to room temperature. The reaction mixture was diluted with THF (20 mL) and quenched with Na2SO4.10H2O followed by a few drops of water. The mixture was stirred at room temperature for 18 h, then filtered through a pad of Celite topped with silica gel. The pad was washed with ethyl acetate and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 45-80% ethyl acetate in hexanes. The desired fractions were concentrated to give (6-(3,4-dichlorobenzylamino)pyridin-3-yl)methanol as a white solid (0.46 g, 57%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.91 (1H, d, J=1.76 Hz), 7.40-7.52 (3H, m), 7.26 (1H, dd, J=8.28, 2.01 Hz), 6.51-6.59 (1H, m), 4.50 (2H, s), 4.44 (2H, s). LCMS: R.T.=2.74; [M+H]+=282.99.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[Ce].CO>COCCOC>[CH:4]1[C:5]2[CH2:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: c1ccc2cc3ccccc3cc2c1
Agent: [Ce]
Solvent: COCCOC
Solvent: CO
Product: c1ccc2c(c1)Cc1ccccc1C2
Yield: 59 %

Procedure:
1.14 mmole of anthracene is reacted with 4.57 m atoms of cerium as powder in 7.5 ml of DME in the conditions of example 9 with application of ultrasound, thus producing anthracenecerium. After action of a methanol excess and the usual treatment, 9,10-dihydroanthracene was isolated with a yield of 59%.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH2:4].CC(C)=O.C([O-])([O-])=O.[K+].[K+].[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[Cl:1][C:2]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:5][C:3]=1[NH:4][C:28](=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1cc(OCCN2CCCCC2)ccc1Cl
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C=Cc1ccccc1)Nc1cc(OCCN2CCCCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
2-chloro-5-(2-piperidinoethoxy)aniline (500 mg, 1.9 mmol, 1 eq.) was placed in mixture of acetone (653 μL) and water (852 μL) in the presence of K2CO3(541 m g, 3.9 mmol, 2 eq.). Cinnamoyl chloride (326 mg, 1.9 mmol, 1 eq.) was then added at 0° C. The reaction mixture was allowed to warm-up to room temperature, stirred for 2 hours and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford N-(2-chloro-5-(2-(piperidin-1-yl)ethoxy)phenyl)cinnamamide (521 mg, 69%).
Reaction SMILES: CON(C)[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[Cl:12].[Br:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][N:17]=1>>[Br:15][C:16]1[N:17]=[CH:18][C:19]([C:4]([C:5]2[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=2[Cl:12])=[O:13])=[CH:20][CH:21]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CON(C)C(=O)c1cc(Br)ccc1Cl
Product: O=C(c1ccc(Br)nc1)c1cc(Br)ccc1Cl

Procedure:
The above N-methoxy-N-methyl-5-bromo-2-chlorobenzamide and 2,5-dibromopyridine were treated in a manner similar to Reference Example 31-(4) to give 5-bromo-2-chlorophenyl 6-bromo-3-pyridyl ketone as a pale yellow solid. APCI-Mass m/Z 374/376 (M+H).
Reaction SMILES: [N:1]1([C:7](=[S:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[C:8]([C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[S:11])[C:9]#[N:10])=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: N#CCC(=S)N1CCOCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(C=C(C#N)C(=S)N2CCOCC2)cc1
Temperature: 50 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-morpholin-4-yl-3-thioxopropanenitrile (0.122 g, 0.72 mmol) and p-anisaldehyde (0.1 mL, 0.86 mmol) in 10% piperidine/ethanol (5.5 mL) was allowed to stir at 50° C. under nitrogen for 3.5 h. The reaction mixture was concentrated and the residue was diluted with 10% citric acid solution and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3 and brine, dried over MgSO4, filtered and concentrated to give 3-(4-methoxyphenyl)-2-(morpholin-4-ylcarbonothioyl)acrylonitrile. The crude product was a mixture of stereoisomers and was used directly in the next step. LCMS: (AA) ES+ 289.
Reaction SMILES: [CH3:1][C:2]12[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[CH:6]1[CH2:5][CH2:4][C:3]2=[CH:22][CH2:23]O.C(Br)(Br)(Br)[Br:26]>>[CH3:1][C:2]12[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([CH2:12][CH2:13][C:14]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=3[CH3:21])[CH:6]1[CH2:5][CH2:4][C:3]2=[CH:22][CH2:23][Br:26]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(O)cc1CCC1CC(=O)CC2(C)C(=CCO)CCC12
Product: Cc1ccc(O)cc1CCC1CC(=O)CC2(C)C(=CCBr)CCC12

Procedure:
Following the general procedure of EXAMPLE 15 and making noncritical variations but starting with 3a-methyl-7-[2-(5-hydroxy-2-methylphenyl)-ethyl]-3-(2-hydroxyethylidene)-octahydro-5H-inden-5-one (EXAMPLE 13) and using carbon tetrabromide in place of carbon tetrachloride, the title compound is obtained, MS (EI) 392 and 390; NMR (CDCl3) 0.94, 1.61-2.1, 2.20, 2.3-2.8, 2.94, 4.0-4.2, 4.9, 5.4-5.5, 6.5-6.7 and 6.99 δ.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:3]=1.[F:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)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>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:3][C:2]([C:36]2[CH:37]=[N:38][C:33]([F:32])=[CH:34][CH:35]=2)=[N:7][CH:6]=1)#[N:25]
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(Cl)cc1-c1cccnc1
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: CN(C)C=O
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1Oc1cnc(-c2ccc(F)nc2)cc1-c1cccnc1
Reaction time: 0.17 h
Yield: 28.3 %

Procedure:
10 mg (0.02 mmol) of 4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.5 mg (0.03 mmol) of (6-fluoropyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 3 mg (27% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:14][NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[C:11]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.C(N(CC)CC)C.[N-:44]=[N+:45]=[N-:46].[Na+]>CC1C=CC=CC=1C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:14][NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]4[NH:46][N:45]=[N:44][N:21]=4)=[CH:18][CH:17]=3)[C:11]3[CH:30]=[C:31]([F:35])[C:32]([F:34])=[CH:33][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(NCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(CNc3ccc(-c4nnn[nH]4)cc3)C3CCCCC3)c2cc1F
Temperature: 145 °C

Procedure:
To a suspension of 0.08 g (0.16 mmol) 4-{2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethylamino}-benzonitrile in 2 ml o-xylene were added 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mmol) sodium azide. The resulting mixture was heated to 145° C. After 72 h another 0.112 g (0.81 mMol) triethylamine hydrochloride and 0.053 g (0.82 mMol) sodium azide were added and the temperature of the oil bath was elevated to 160° C. After 24 h the oil bath was removed and the reaction mixture was poured on saturated aqueous ammonium chloride solution. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The resulting light brown solid was dissolved in ethyl acetate. Upon evaporation a suspension formed which was filtered and washed with ethyl acetate. The resulting solid was taken up in 2 ml acetonitrile, heated to reflux and then cooled down to 4° C. The suspension was filtered, the solid washed with acetonitrile and dried under high vacuum. Light brown solid (25%). MS (Turbo Spray): m/z=534.2 [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C@@H:9]([CH3:13])[CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1.[OH:14]S(O)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C@@H:9]([CH3:13])[CH2:10][C:11]([NH2:12])=[O:14])=[CH:6][CH:7]=1
Reactant: C[C@@H](CC#N)Nc1ccc(Br)cc1
Reactant: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](CC(N)=O)Nc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
(3S)-3-[(4-bromophenyl)amino]butanenitrile (for a preparation see Intermediate 32) (17.3 g, 72.4 mmol) was taken up in Toluene (500 ml) and H2SO4 (19.28 ml, 362 mmol) added. The biphasic mixture was stirred at 60° C. After two hours, only a small amount of SM remained by LCMS so the reaction was diluted with water (500 ml) and the phases separated. The aqueous phase was basified with 10N NaOH and extracted with EtOAc (2×750 ml). The combined organics were dried with Na2SO4, filtered and concentrated to yield the product as a cream solid (17.5 g). LCMS (Method B): Rt=0.77, MH+=257
Reaction SMILES: [CH3:1][C:2]([OH:13])([CH3:12])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1.[CH3:14][Si:15](Cl)([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[CH3:12][C:2]([O:13][Si:15]([CH3:17])([CH3:16])[CH3:14])([CH3:1])[CH2:3][N:4]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[N:5]1
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)(O)Cn1cc([N+](=O)[O-])cn1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(Cn1cc([N+](=O)[O-])cn1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a solution of 2-methyl-1-(4-nitro-1H-pyrazol-1-yl)propan-2-ol (1 equiv) in dry DMF (0.18 M) was added trimethylsilyl chloride (1.26 equiv) at 0° C. and imidazole (2.55 equiv) under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 4 h and then diluted with ethyl acetate. The organic solution was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as a yellow oil (75.5% yield). 1H NMR (400 MHz, CHLOROFORM-d1) δ ppm (9.06 (bs, 1H), 7.91 (s, 1H), 4.13 (s, 3H), 3.79 (s, 2H), 1.70 (s, 9H), 1.68 (s, 6H). MS (ESI) m/z 258.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N12CCCN=C1CCCCC2.[NH2:17][C:18]1[N:39]=[C:38](Cl)[CH:37]=[CH:36][C:19]=1[C:20]([NH:22][CH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:27][CH:28]=1)=[O:21].C1C=CC(CC(NCN[C@H](C(O)=O)CC2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1>CS(C)=O>[NH2:17][C:18]1[N:39]=[C:38]([NH:1][CH2:2][C:3]([OH:5])=[O:4])[CH:37]=[CH:36][C:19]=1[C:20](=[O:21])[NH:22][CH2:23][C:24]1[S:25][C:26]([O:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:27][CH:28]=1
Reactant: NCC(=O)O
Reactant: Nc1nc(Cl)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Agent: O=C(Cc1ccccc1)NCN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(NCC(=O)O)ccc1C(=O)NCc1ccc(Oc2ccccc2)s1
Temperature: 190 °C
Reaction time: 4 h
Yield: 20 %

Procedure:
Glycine (610 mg, 8.13 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (405 μl, 2.71 mmol) were added to 2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in Example A-101 (195 mg, 0.542 mmol) under nitrogen atmosphere, and the solution was stirred at 190° C. for 4 hours. Dimethylsulfoxide (5 mL) was added to the reaction mixture, which was then filtered with a polytetrafluoroethylene membrane filter (Whatman Inc), the filtrate was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), title compound (55.36 mg, 0.108 mmol, 20%) was obtained.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1.C[Si]([C:19]#[CH:20])(C)C.N1C=CC=CC=1>C(N(CC)CC)C>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:19]#[CH:20])=[CH:10][CH:9]=1
Reactant: Ic1ccc(OCC2OCCO2)cc1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C#Cc1ccc(OCC2OCCO2)cc1
Yield: 83 %

Procedure:
1-[(1,3-Dioxolan-2-yl)methyloxy]-4-iodobenzene (36.3 g) and trimethylsilylacetylene (50.0 g) were reacted in the presence of bistriphenylphosphinepalladium dichloride (2.50 g) and cuprous iodide (1.25 g), in triethylamine (140 ml) and pyridine (70 ml) at 60° C. for 2 hr. The reaction solution was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and concentrated. The resulting residue was dissolved in methanol and treated with 2N sodium hydroxide, to give 20.1 g of the title compound.
Reaction SMILES: C([O:8][N:9]1[CH:12]([CH2:13][O:14]CC2C=CC=CC=2)[CH:11]([N:22]2[CH:37]=[CH:36][C:26]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][C:23]2=[O:24])[C:10]1=[O:38])C1C=CC=CC=1.[H][H]>CO.[Ni]>[OH:8][N:9]1[CH:12]([CH2:13][OH:14])[CH:11]([N:22]2[CH:37]=[CH:36][C:26]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:25][C:23]2=[O:24])[C:10]1=[O:38]
Reactant: [H][H]
Reactant: O=C(Nc1ccn(C2C(=O)N(OCc3ccccc3)C2COCc2ccccc2)c(=O)n1)c1ccccc1
Agent: [Ni]
Solvent: CO
Product: O=C(Nc1ccn(C2C(=O)N(O)C2CO)c(=O)n1)c1ccccc1

Procedure:
1-N-Benzyloxy-3-(N-benzoylcytosin-1-yl)-4-benzyloxymethyl-2-azetidinone (10mmole) is taken up in methanol (50 ml) and hydrogenated using Raney nickel (5 g) and hydrogen at a pressure of 40 psi for 6 hours. The reaction mixture is filtered, the catalyst washed with methanol (20 ml) and the combined fractions are concentrated to afford the product as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH2:12]([O:14][C:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16])[CH3:13].[F-].[K+]>CN(C=O)C.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>[CH2:15]([O:14][C:12]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)=[CH2:13])[CH3:16]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
A solution of 2-chloro-4-trifluoromethylpyridine (3.33 g), (1-ethoxyvinyl)tri-n-butyltin (5.95 g) and bis(triphenylphosphine)palladium(II) chloride (0.4 g) in DMF (40 ml) was heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature, potassium fluoride (60 ml of a 10% aqueous solution) was added and the resulting mixture was stirred for 1 hour then filtered through Hyflo supercel filter aid which was rinsed through with ether. The filtrate was extracted with ether (×2) and the combined extracts were washed with brine, then dried, concentrated and chromatographed using ether:hexane 1:4 as the eluant to give 1-ethoxy-1-(4-trifluoromethylpyrid-2-yl)-ethylene (1.4 g, 35% yield) as a pale yellow liquid; 1H NMR (270 MHz): δ1.45(3H,t), 4.00(2H,q), 4.42(1H,d), 5.50(1H,d), 7.40(1H,d), 7.88(1H,s), 8.72(1H,d) ppm.