Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[CH:6]=1)[NH2:3]
Reactant: OC1CN(c2cc(Cl)ncn2)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1cc(N2CC(O)C2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 27.2 ml (27.9 g, 279.1 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 10.4 g (55.8 mmol) of 1-(6-chloropyrimidin-4-yl)azetidin-3-ol in 100 ml of ethanol. The reaction solution is stirred at 80° C. for 16 h. For work-up, the mixture is concentrated under reduced pressure, and the precipitate is filtered off and washed twice with in each case 10 ml of ethanol. Yield: 2.0 g (19% of theory)
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34][CH2:35][O:36][CH3:37])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34][CH2:35][O:36][CH3:37])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([O:5][CH2:4][CH3:3])=[O:7])[CH3:19]
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(C)=C/c1cc(OC)c(OCOC)c2c(CC)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:33][CH:34]([Cl:38])[C:35]([NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][N:14]=[N:13][CH:12]=3)[CH2:7][S:8][C@H:3]12)=[O:36]
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3cnn[nH]3)CS[C@H]12
Reactant: O=C(Cl)C(Cl)Cl
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(O)C1=C(CSc2cnn[nH]2)CS[C@@H]2C(NC(=O)C(Cl)Cl)C(=O)N12
Temperature: -7.5 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
7-Amino-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.98 g) was suspended in methylene chloride (10 ml) and bis(trimethylsilyl)acetamide (2.53 g) was added to the suspension to give a solution. To the solution was added dropwise a solution of dichloroacetyl chloride (0.46 g) in methylene chloride (10 ml) at -30° C. The mixture was stirred at -10°0 to -15° C for 30 minutes and then concentrated under reduced pressure. To the residue was added ethyl acetate (50 ml) and water (30 ml) and the mixture was stirred and filtered. The ethyl acetate layer was separated from the filtrate and concentrated under reduced pressure to a half of volume. Water (30 ml) was added to the concentrated solution and the mixture was adjusted to pH 7.2 by adding aqueous sodium bicarbonate under cooling and stirring. The aqueous layer was separated from the mixture, adjusted to pH 6 with diluted hydrochloric acid, washed with ethyl acetate, adjusted to pH 2 with diluted hydrochloric acid and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and treated with activated charcoal powder. Ethyl acetate was distilled off from the solution under reduced pressure. The residue was pulverized by treating with ether and precipitates were collected by filtration to give 7-dichloroacetamido-3-(1H-1,2,3-triazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (0.56 g). The solvent was distilled off from the mother liquid under reduced pressure and the residue was pulverized by treating with diisopropyl ether. Precipitates were collected by filtration to give the same product (0.14 g). Total yield was 0.70 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1.[Li]CCCC.[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:33][C:32]1=[O:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[CH2:23]([O:30][C@@H:31]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:35]([O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[C@@H:34]([CH2:53][O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[O:33][C:32]1([C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)[CH:3]=1)[OH:62])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=Cc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=Cc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-vinylbenzyl)benzene (intermediate AM) (215 mg) in toluene:THF (2:1) (3 mL) at −78° C. was added n-BuLi (0.34 mL, 2.5 M in hexane) dropwise. After 45 min, the above mixture was added dropwise into a pre-cooled (−78° C.) solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one (453 mg) in toluene (3 mL). After being stirred for 2.5 h at −78° C., the reaction mixture was quenched by saturated NH4Cl and diluted with ethyl acetate. The organic layer was separated, washed with brine and dried over Na2SO4. Concentration gave the crude product which was purified by chromatography to provide intermediate AN (712 mg) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.CO/[CH:14]=[CH:15]/[C:16]([O:18][Si](C)(C)C)=[CH2:17].CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.[Eu]>>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:17][C:16](=[O:18])[CH:15]=[CH:14][O:8]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Eu]
Product: Cn1ncc([N+](=O)[O-])c1C1CC(=O)C=CO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (600 mg, 3.87 mmol) in CDCl3 (20 mL) was added Danishefsky's diene (836 mg, 5.81 mmol) and Resolve-Al™ EuFOD (157 mg, 0.39 mmol). The reaction mixture was heated at 80° C. in a sealed tube for 24 hr. Additional Resolve-Al™ EuFOD (250 mg, 0.62 mmol) was added and heating continued for another 24 hr. The reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2H-pyran-4(3H)-one a yellow solid (710 mg, 82%). A portion of this solid (300 mg, 1.35 mmol) was dissolved in THF (10 mL) under nitrogen and cooled to −78° C. A solution of L-selectride (1 M in THF, 1.48 mL, 1.48 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min. The mixture was quenched with MeOH (2 mL) and warmed to room temperature. EtOAc (30 mL) and brine (30 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (3×20 mL) then the combined organic layers were washed with brine (30 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-(2-methyl-4-nitro-pyrazol-3-yl)tetrahydropyran-4-one as a colourless solid (224 mg, 61% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.70 (dd, J=11.8, 3.3 Hz, 1H), 4.49 (ddd, J=11.8, 7.5, 1.3 Hz, 1H), 4.15 (s, 3H), 3.94-3.86 (m, 1H), 2.83-2.63 (m, 3H), 2.58-2.50 (m, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9]C2CCCCO2)[CH:6]=1.[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36](B5OC(C)(C)C(C)(C)O5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]>>[CH:16]([N:19]1[C:23]([C:24]2[S:25][C:26]3[CH2:27][CH2:28][O:29][C:30]4[CH:37]=[C:36]([C:2]5[N:3]=[CH:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=5)[CH:35]=[CH:34][C:31]=4[C:32]=3[N:33]=2)=[N:22][CH:21]=[N:20]1)([CH3:18])[CH3:17]
Reactant: Brc1cn(CCOC2CCCCO2)cn1
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(B3OC(C)(C)C(C)(C)O3)ccc1-2
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(-c3cn(CCO)cn3)ccc1-2

Procedure:
Following the procedure for 258, 4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-imidazole was reacted with 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene to give 486. MS (ESI+) 423.1. 1H NMR (400 MHz, DMSO) δ 8.32 (d, J=8.3, 1H), 8.11 (s, 1H), 7.73 (d, J=1.0, 1H), 7.68 (d, J=0.9, 1H), 7.58 (dd, J=8.3, 1.7, 1H), 7.44 (d, J=1.7, 1H), 5.95-5.74 (m, 1H), 5.00 (t, J=5.2, 1H), 4.39 (t, J=5.0, 2H), 4.03 (t, J=5.4, 2H), 3.70 (q, J=5.3, 2H), 3.44 (t, J=5.0, 2H), 1.56 (d, J=6.6, 6H)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@@H:23](O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][C@H:23]([O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Reaction time: 42 h

Procedure:
6.0 g (33.3 mmol) of ethyl 4-hydroxyphenylacetate, 6.25 g (33.3 mmol) of (3R)-1-(t-butoxycarbonyl)-3-hydroxypyrrolidine and 10.5 g (40 mmol) of triphenylphosphine were dissolved in 125 ml of tetrahydrofuran. 6.3 ml (40 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred for 42 hours. After the same isolation process as that of step 1 in Example 1 with ethyl acetate as the extractant, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.O=[C:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: NCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of (3-bromophenyl)methanamine (670 mg, 3.6 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (600 mg, 3 mmol) and sodium triacetoxyborohydride (1.27 g, 6 mmol) in 10 mL of dichloromethane was added acetic acid (360 mg, 6 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel, eluting with petroleum ether:EtOAc=3:1) to give tert-butyl 4-(3-bromobenzylamino)piperidine-1-carboxylate (0.9 g, 68%) as an oil. 1H NMR (300 MHz, CDCl3) δ 7.48-7.47 (m, 1H), 7.38-7.35 (m, 1H), 7.25-7.17 (m, 2H), 4.10 (brs, 1H), 3.79 (s, 2H), 2.85-2.76 (m, 2H), 2.67-2.61 (m, 1H), 1.87-1.82 (m, 2H), 1.45 (s, 9H), 1.37-1.29 (m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:10].C(=O)([O-])[O-].[Na+].[Na+].[N:17]([C:20]1[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=1[CH3:28])=[C:18]=[S:19]>C(O)C>[NH2:10][C:4]1[C:3]([NH:2][CH3:1])=[C:8]([NH:9][C:18]([NH:17][C:20]2[C:21]([CH3:28])=[CH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[S:19])[CH:7]=[CH:6][CH:5]=1
Reactant: CNc1c(N)cccc1N
Reactant: Cc1cc(C)c(N=C=S)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CNc1c(N)cccc1NC(=S)Nc1c(C)cc(C)cc1C
Yield: 59.4 %

Procedure:
To a mixture containing 0.25 g (1.82 mmol) of N2-methylbenzene-1,2,3-triamine and 0.40 g (3.7 mmol) of sodium carbonate in ethanol was added 0.32 g (1.86 mmol) of 2-isothiocyanato-1,3,5-trimethylbenzene. The reaction was heated at reflux and the solvent was removed under reduced pressure. Purification of the residue via Biotage chromatography eluting with 20% ethyl acetate/dichloromethane gave 0.34 g (60%) of product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[C:22]#[N:23].[I:24]N1C(=O)CCC1=O.C(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[C:7]([I:24])=[C:6]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH3:14])[CH3:15])[CH2:9]2)[C:5]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: CN(C)[C@H]1CCN(c2cc(N)c(C#N)cc2-c2ccccc2)C1
Reactant: O=C1CCC(=O)N1I
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN(C)[C@H]1CCN(c2c(-c3ccccc3)cc(C#N)c(N)c2I)C1
Reaction time: 6 h
Yield: 62 %

Procedure:
4-Amino-6-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]biphenyl-3-carbonitrile (I-243) (75 mg, 0.25 mmol) was dissolved in acetic acid (1 ml), and at room temperature, N-iodosuccinimide (66 mg, 0.29 mmol) was added. After stirring under nitrogen atmosphere at the same temperature for 6 hours, the reaction liquid was fractionated with chloroform and aqueous 1 M sodium hydroxide solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=9:1) to obtain the entitled compound (67 mg, 63%) as a brown gel.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][O:8][C:4]=2[CH:3]=1.[NH2:15][C@@H:16]([CH3:31])[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>CO>[NH2:15][C@@H:16]([CH3:31])[C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].[OH:1][C:2]1[CH:14]=[CH:13][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Agent: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
(6-Hydroxy-1-benzofuran-3-yl)acetic acid (25 g), dichloro[(+)-1,2-bis((2R,5R)-2,5-diisopropylphosphorano)benzene]ruthenium (II)-N,N-dimethylformamide complex (19.1 mg) and (S)-2-amino-1,1-diphenylpropan-1-ol (29.5 g) were weighted in an autoclave and substituted with argon. Dehydrated methanol (250 mL) was added and the mixture was purged with hydrogen, pressurized under a hydrogen pressure (1.0 MPa), and reacted at 35° C. for 15 hr. The reaction mixture was concentrated under reduced pressure, methanol (109 mL) and N,N-dimethylformamide (27 mL) were added, and the mixture was dissolved by heating at 50° C. Isopropyl ether (200 mL) was added dropwise at 60° C., seed crystal was added, and isopropyl ether (369 mL) was added dropwise. The mixture was cooled to room temperature, stirred for 4 hr and stirred for 1 hr under ice-cooling, and the solid was collected by filtration. The solid was dried at 60° C. under reduced pressure to give the title compound (38.98 g). 99.8% de.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cccc(O)c1C
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Yield: 86.9 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (20 mL) were added ethyl 3-(3-hydroxy-2-methylphenyl)propanoate (197 mg) and cesium carbonate (511 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.C[N:16](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:16])=[O:8])=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(N)=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice cooled suspension of 4-methoxy-2-nitro-benzoic acid (14.1 g, 71.5 mmol) and some drops of DMF in DCM (150 ml) was added drop wise oxalyl chloride (19.0 g, 150 mmol) and the mixture was stirred for two hours at room temperature. The solvent was evaporated and water was added. The product was filtered of and washed with water and hexane. The product was dried in vacuum. Yield: 10 g, 71%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[CH:13][N:12]=1.[H-].[Na+]>>[Cl:10][C:11]1[N:16]=[C:15]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(Sc2ccnc(Cl)n2)cc1

Procedure:
The 2-chloro-4-(4-methoxyphenylsulphanyl)pyrimidine was prepared in a similar manner to the analogous starting material of Example 1, from 4-methoxybenzenethiol (1.90 g, 13.4 mmol), 2,4-dichloropyrimidine (2.0 g, 13.4 mmol) and sodium hydride [60% dispersion in oil] (590 mg, 14.8 mmol) as an off-white solid m.p. 69-70°.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1([CH3:16])[O:13][CH:12]([CH2:14][NH2:15])[CH2:11][O:10]1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[N:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:15][CH2:14][CH:12]3[CH2:11][O:10][C:9]([CH3:16])([CH3:8])[O:13]3)=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[N:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC1(C)OCC(CN)O1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CNc2c([N+](=O)[O-])cnc3cc(OCc4ccccc4)ccc23)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.2 %

Procedure:
Triethylamine (31.88 mL, 228.77 mmol) followed by 2,2-dimethyl-1,3-dioxolan-4-methanamine (20.0 g, 152.51 mmol) were added to a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (48.00 g, 152.51 mmol) in dichloromethane (400 mL), which was then stirred at ambient temperature for 6 hours. The crude reaction mixture was concentrated under reduced pressure, and the resulting solid was treated with water. The mixture was stirred for 1 hour. The solid was collected by filtration, washed with water, dried, suspended in diethyl ether (400 mL), sonicated, and the resulting precipitate material was collected by filtration. The product was dried under vacuum at 40° C. for 12 hours to afford 60.1 g of (7-benzyloxy-3-nitro-quinolin-4-yl)[(2,2-dimethyl[1,3]dioxolan-4-yl)methyl]amine as a yellow solid, mp 154-155° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=2)=[CH:32][CH:33]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
Reactant: OB(O)c1ccc(F)nc1
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: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccc(F)nc3)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 56.4 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 2-fluoropyridine-5-boronic acid (0.072 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.015 g) to obtain the title compound (0.070 g) as a colorless solid. MS (ISP): 485.3 (M+H)+
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 10 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of methyl indole-6-carboxylate (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10° C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane—ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.