Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([CH3:11])=[C:6](C(O)=O)[C:5]=1[CH3:15])([O-:3])=[O:2].Cl.[CH2:17]([OH:19])[CH3:18].C([OH:22])C>>[N+:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([C:11]([O:19][CH2:17][CH3:18])=[O:22])=[CH:8][C:9]=1[CH3:10])([O-:3])=[O:2]
Reactant: CCO
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1C(=O)O
Agent: Cl
Product: CCOC(=O)c1cc(C)c([N+](=O)[O-])c(C)c1

Procedure:
To a solution of 4-nitromesitylenecarboxylic acid (13 g) in ethanol (50 ml) was added a solution of 28% hydrochloric acid-ethanol (50 ml) and the mixture was refluxed under heating for 2 hr. There action mixture was concentrated and ethyl acetate was added. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=9:1) to give the title compound (7.7 g) as pale-brown crystals.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:2]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:38])(=O)=O)=CC=1>C1COCC1.CCCCCC>[C:1]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8]([F:38])=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=2)[CH:2]=1
Reactant: COc1cc(-c2cccc(-c3ccccc3)c2)cnc1OC
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ncc(-c2cccc(-c3ccccc3)c2)c(F)c1OC
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 29 %

Procedure:
To a solution of 5-(biphenyl-3-yl)-2,3-dimethoxypyridine (52 mg, 0.178 mmol) in THF (2 mL) at −78° C. was added n-BuLi solution in hexane (2.5 M, 0.157 mL) and then the −78° C. bath was replaced with a 0° C. cooling bath. After stirring at this temperature for 50 min, the reaction mixture was cooled down to −78° C. and then solid N-fluorobenzenesulfonimide was added to it. The reaction was quenched after 10 min by adding saturated aqueous NH4Cl solution and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. Layers were separated and the aqueous solution was extracted with EtOAc (2×). Combined organic solutions were dried over Na2SO4 and concentrated. Purification by preparative HPLC (10-85% CH3CN/H2O over 20 min, 0.05% added TFA) afforded 16 mg (29%) of 5-(biphenyl-3-yl)-4-fluoro-2,3-dimethoxypyridine as a colorless viscous material. LC/MS (M+H)+ 310.2.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[C-:20]#[N:21].[Li+]>CN(C=O)C>[C:20]([C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:21]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1Cl
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2Cl)c1C#N
Temperature: 0 °C
Yield: 60.4 %

Procedure:
A solution of 6.4 g of 5-chloro-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester and 2 g of lithium cyanide dissolved in 30 ml of DMF was reacted at approximately 110° C. for 23 hours. One additional gram of lithium cyanide was added to the reaction mixture which was heated for an additional 7 hours. The mixture was poured into ice water and the precipitated solid was collected by filtration and recrystallized from 3A alcohol (charcoal) to provide 3.75 g of 5-cyano-1-(2,4-dichlorophenyl)-1H-pyrazole-4-carboxylic acid, ethyl ester. Yield 61%. mp=79°-81° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1Br)[CH2:2]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:19])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:26]1[CH:25]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:27]=1)[CH2:2]2
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2ccccc2NC(=O)OC2CN3CCC2CC3)c1
Yield: 85 %

Procedure:
Using general procedure E, quinuclidin-3-yl2-bromophenylcarbamate, 3-methoxyphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (120 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 8.08 (br s, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.5, 1.5 Hz, 1H), 7.13 (td, J=7.5, 1.5 Hz, 1H), 6.96 (dd, J=8.0, 2.0 Hz, 2H), 6.91 (t, J=1.5 Hz, 1H), 6.73 (br s, 1H), 4.79 (m, 1H), 3.84 (s, 3H), 3.24 (m, 1H), 2.90-2.70 (m, 5H), 2.05 (m, 1H), 1.80-1.70 (m, 2H), 1.62-1.52 (m, 1H), 1.41-1.32 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 160.1, 153.4, 139.5, 134.7, 131.5, 130.1, 130.1, 128.5, 123.5, 121.4, 119.9, 114.7, 113.6, 72.1, 55.3, 55.3, 47.3, 46.5, 25.3, 24.5, 19.4 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.48 min; (M+1) 353
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=[CH:53][C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(N)(CC)C>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH:48]([CH3:53])[CH2:49][CH3:50])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCC(C)N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)NC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.3 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27.3 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and sec-butylamine (12.12 uL, 0.08 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (3.2 mg, 9%). LC-MS m/z 577 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:10])[C:7]=1[Cl:8].[N+:16]([O-])([OH:18])=[O:17]>>[Cl:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:10])[C:7]=1[Cl:8]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1c(Cl)c(Cl)cc2c1OCCO2
Product: CC(=O)c1c(Cl)c(Cl)c([N+](=O)[O-])c2c1OCCO2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
5',6'-Dichloro-2',3'-ethylenedioxyacetophenone (8.5 g, 0.0344 miol) was added in portions to 34.5 mL of stirring fuming nitric acid at a rate such that the temperature of the reaction mixture remained below 10° C. The mixture was stirred for an additional 10 minutes at 5 C. and then poured onto 250 g of crushed ice giving yellow precipitate. The precipitate was isolated by filtration and washed with water. Drying gave 5',6'-dichloro-2',3'-ethylenedioxy-4'-nitroacetophenone (8.9 g, 0.0341 mol), m.p. 181°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:31])([F:30])[F:29])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]([F:29])([F:30])[F:31])[CH:22]=3)[N:9]=2)=[CH:4][C:3]=1[CH2:13][NH:14][C:15](=[O:18])[O:16][CH3:17]
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Reactant: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)NCc1cc(-c2ccn(Cc3cccc(OC(F)(F)F)c3)n2)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of methyl N-[[2-chloro-5-(1H-pyrazol-3-yl)phenyl]methyl]carbamate (i.e. the product of Step B, Example 4) (0.2 g, 0.75 mmol), 1-(bromomethyl)-3-(trifluoromethoxy)benzene (0.765 g, 3.0 mmol) and potassium carbonate (−325 mesh, 0.829 g, 6.0 mmol) in N,N-dimethylformamide (4 mL) was heated at 100° C. overnight and then concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.178 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:31].[Na+].O.OP([O-])(O)=O.[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:31])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:23][OH:24])[CH2:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)cc3)cc12
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(C4(CO)CCC4)cc3)cc12
Temperature: 0 °C
Reaction time: 24 h
Yield: 29.3 %

Procedure:
To a mixture of 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carbaldehyde (80 mg, 0.24 mmol) in acetonitrile (6 mL) and tert-butanol (6 mL) was added 2-methyl-2-butene (3 mL). The reaction mixture was cooled to 0° C. and treated with a solution of sodium chlorite (420 mg, 4.80 mmol) and sodium phosphate monobasic hydrate (650 mg, 4.80 mmol) in water (3 mL) dropwise via additional funnel. The ice bath was removed, and the reaction mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo to give a residue, which was purified by prep-HPLC (Kromasil Eternity-5-C18 150*30 mm*5 μm Mobile phase: from 35% MeCN in water (0.1% TFA) to 50% MeCN in water (0.1% TFA); Wavelength: 220 nm Flow rate: 30 mL/min) to give 6-chloro-5-{4-[1-(hydroxymethyl)cyclobutyl]phenyl}-1H-indole-3-carboxylic acid (25 mg, 32% yield) as a white solid. MS (ES+) 377.9 (M+Na)+. 1H NMR (400 MHz, CD3OD) δ 8.01 (s, 1H), 7.97 (s, 1H), 7.57 (s, 1 H), 7.39 (d, 2 H), 7.23 (d, 2 H), 3.70 (s, 2H), 2.39-2.30 (m, 4 H), 2.11-2.09 (m, 1 H), 1.92-1.91 (m, 1 H).
Reaction SMILES: Cl.[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([OH:11])=[O:10])=[O:5].[C:34]1([C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N+]=[N-])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)C>CO>[OH:2][C@@H:3]([C@H:18]([OH:33])[C@H:19]([OH:32])[C@@H:20]([NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH2:26])[CH2:21][OH:22])[C:4]([NH:6][C@H:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][C:9]([O:11][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)O)c1ccccc1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CO)[C@@H](O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(=O)OC(c1ccccc1)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.2 %

Procedure:
To a solution of (S)-3-[(2S,3R,4R,5S)-2,3,4,6-tetrahydroxy-5-(L-leucyl)aminohexanoyl]amino-3-phenylpropionic acid hydrochloride (1.84 g) in methanol (40 ml) was added a solution of diphenyldiazomethane (1.45 g) in methanol (20 ml) and the mixture was stirred at room temperature for 4 hours. After addition of acetic acid (0.1 ml), the reaction mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogencarbonate solution and saturated brine respectively and the ethyl acetate solution was dried over anhydrous sodium sulfate. Removal of the organic solvent gave a residue, which was purified by silica gel column chromatography. Elution with ethyl acetate-methnaol (2:1) provided the title compound (2.05 g).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[NH:19])OC)[N:8]=1.[Cl-:23].[NH4+:24]>CO>[ClH:23].[F:1][C:2]([F:22])([F:21])[CH2:3][N:4]=[C:5]([NH2:20])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:24])=[NH:19])[N:8]=1
Reactant: COC(=N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: Cl
Product: N=C(N)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1

Procedure:
A solution of methyl 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valerimidate (1 g.) in MeOH (12 ml.) and ammonium chloride (0.162 g.) was stirred for 3 hours at room temperature. The solvent was removed to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramidine hydrochloride as a yellow gum, which was used without further purification.
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36])(=O)C.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[OH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reaction time: 18 h
Yield: 0.4 %

Procedure:
2-chlorotrityl chloride resin (3.00 g, 4.5 mmol) was swelled in DCM. 4-Acetoxy-3-nitro-benzoic acid (2.53 g, 11.25 mmol) was dissolved in DMF (7.5 ml) and triethylamine (1.56 ml, 11.25 ml) mixed with the drained resin. The mixture was placed on a shaker for 18 h at rt. Followed by a careful wash with DMF (3×2 min) and methanol (3×2 min). The resin was treated with a solution of 2-phanyl-ethyl amine (2M, 10 ml) in dichloromethane for 1 h at rt. and for 3 h at rt. then washed with dichloromethane (3×2 min) and dried. 36.1 mg resin was added 1% TFA in DCM 10 min filtered, added hexane and evaporated to give 4-hydroxy-3-nitro-benzoic acid (7.8 mg), which correspond to a loading of 1.18 mmol/g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].CC(C)([O-])C.[Na+]>CO.C1C=CC=CC=1.C1C=CC=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)c1ccccc1Cl
Agent: Cl[Ru]Cl
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(O)c1ccccc1Cl
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Benzeneruthenium(II) chloride dimer (0.5 mg, 1 μmol, 0.25 mol %) and a chiral ligand (M=Ru, R=t-Bu, Ar=C6H5—, 2.6 μmol, 0.33 mol %) were dissolved in methanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 2 h at 65° C. After the mixture was cooled to room temperature, o-chloroacetophenone (0.8 mmol), methanol (2 mL) and a solution of sodium t-butoxide in methanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 6 h under H2 (40 atm) at 50° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent:ethyl acetate/petroleum ether=1/5). Accordingly, pure 1-(o-chlorophenyl)ethanol was obtained and the ee value (ee=97%) was measured by GC analysis.
Reaction SMILES: C(OC(=O)[N:7]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])(C)(C)C.BrCCCCCC#N>Cl.CCO>[CH2:16]([O:15][N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1=[NH:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(CCCCCC#N)OCc1ccccc1
Agent: Cl
Agent: N#CCCCCCBr
Solvent: CCO
Product: N=C1CCCCCN1OCc1ccccc1
Reaction time: 0.75 h

Procedure:
Tert-butyl-(benzyloxy)-(5-cyanopentyl)-carbamate (synthesized following the procedure described in EXAMPLE 1—Step 1a starting from 6-bromohexanenitrile) was dissolved in a saturated solution of HCl in EtOH and the mixture was stirred for 45 minutes. Nitrogen was bubbled into the solution to remove HCl in excess. The solvent was removed under reduced pressure and the residue, dissolved in 1,4-dioxane, was treated with triethylamine to adjust pH at 10. Ethanol was removed and the title compound containing an excess of triethylammonium chloride and ethyl 6-[(benzyloxy)amino]hexanoate was used without further purification. The analytical sample was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column C18). The pooled product fractions were lyophilized.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][CH3:21]>C(Cl)(Cl)Cl>[CH2:18]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)[CH2:19][CH2:20][CH3:21]
Reactant: OCCN1CCNCC1
Reactant: CCCCBr
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCN1CCN(CCO)CC1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
2-(1-Piperazinyl)ethanol (12.2 g) was dissolved in chloroform (60 ml), triethylamine (13.0 ml) and 1-bromobutane (14.1 g) were successively added at room temperature, and the mixture was stirred overnight. The reaction solution was successively washed with a 10M aqueous solution of potassium hydroxide (15 ml), water (50 ml×2), saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (methylene chloride:methanol:aqueous ammonia=90:10:0.5) to give the title compound (10.8 g) as a pale yellow oily substance. Yield=62%.
Reaction SMILES: CCN(C(C)C)C(C)C.CC([O:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[C:23]([OH:25])=O)=[O:16])(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:50][CH2:51][C:52]1[CH:53]=[C:54]([CH2:58][N:59]2[C:67]3[C:62](=[C:63]([C:68]([OH:71])([CH3:70])[CH3:69])[CH:64]=[CH:65][CH:66]=3)[C:61]([NH:72][S:73]([C:76]3[S:77][C:78]([Cl:81])=[CH:79][CH:80]=3)(=[O:75])=[O:74])=[N:60]2)[CH:55]=[CH:56][CH:57]=1.Cl.O1CCOCC1>C(Cl)Cl>[CH:15]([OH:16])=[O:14].[Cl:81][C:78]1[S:77][C:76]([S:73]([NH:72][C:61]2[C:62]3[C:67](=[CH:66][CH:65]=[CH:64][C:63]=3[C:68]([OH:71])([CH3:69])[CH3:70])[N:59]([CH2:58][C:54]3[CH:53]=[C:52]([CH2:51][NH:50][C:23]([C@H:18]4[CH2:19][O:20][CH2:21][CH2:22][NH:17]4)=[O:25])[CH:57]=[CH:56][CH:55]=3)[N:60]=2)(=[O:74])=[O:75])=[CH:80][CH:79]=1
Reactant: CC(C)(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: CC(C)(C)OC(=O)N1CCOC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(O)c1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)[C@H]2COCCN2)c1
Product: O=CO
Temperature: 25 °C
Yield: 5 %

Procedure:
DIPEA (0.057 mL, 0.326 mmol) was added to a stirring solution of (3R)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-morpholinecarboxylic acid (18.84 mg, 0.081 mmol) in DCM (1 mL). HATU (31.0 mg, 0.081 mmol) was then added, followed by N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(1-hydroxy-1-methylethyl)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 78) (40 mg, 0.081 mmol) and the reaction was stirred for an hour at room temp. The reaction mixture was concentrated and 4N Hydrogen chloride in dioxane (0.020 mL, 0.081 mmol) was then added and the reaction stirred at room temperature for 0.5 h. The reaction mixture was passed through a pre-conditioned (MeOH)SCX-2 cartridge, washed with methanol and then eluted using 2M ammonia in methanol. The appropriate ammoniacal fractions were concentrated, and the residue was dissolved in DMSO (0.5 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was removed under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (2.7 mg, 5%). LCMS (System F) RT=0.84 min, ES+ve m/z 604/606 (M+H)+.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[N:23]=[C:22]([NH2:27])[N:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([F:26])[N:23]=[C:22]([NH:27][CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][C:5]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:21]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: ClCc1c(-c2ccccc2)nc2ccccn12
Agent: Cl
Product: Fc1cc(F)nc(NCc2c(-c3ccccc3)nc3ccccn23)n1
Yield: 17 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. (0.10 g, 17% yield), M/e− 338.2 for C18H13F2N5 (M+H)+
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:38]=[CH:37][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][NH:33][C@@H:32]([CH3:36])[CH2:31]3)=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[N+:39]([C:42]1[CH:55]=[CH:54][C:45]([CH2:46][O:47][C:48]([NH:50][C:51](=N)[CH3:52])=[O:49])=[CH:44][CH:43]=1)([O-:41])=[O:40]>C(#N)C>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][S:9][C@@H:10]2[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)=[O:16])[C@H:12]([C:28]([N:30]3[CH2:35][CH2:34][N:33]([C:51](=[N:50][C:48]([O:47][CH2:46][C:45]4[CH:54]=[CH:55][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=4)=[O:49])[CH3:52])[C@@H:32]([CH3:36])[CH2:31]3)=[O:29])[CH2:11]2)=[CH:37][CH:38]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN[C@@H](C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC(=N)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(C)=NC(=O)OCc4ccc([N+](=O)[O-])cc4)[C@@H](C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 30.8 %

Procedure:
2.26 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[(3S)-3-methylpiperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine hydrochloride [prepared as described in step (i) above] were mixed with 1.14 g of N-(4-nitrobenzyloxycarbonyl)acetamidine and 45 ml of acetonitrile, and the mixture was heated under reflux for 16 hours. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Preparation 1(ii), to give 922 mg of the title compound, as a powder.
Reaction SMILES: [CH:1]1([C:7]2[C:8](C3CCCCC3)=[C:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:26]([OH:29])(=[O:28])=[O:27].[OH-].[Na+:31].[CH2:32](O)[CH3:33]>C(Cl)Cl>[CH:13]1([C:9]2([S:26]([O-:29])(=[O:28])=[O:27])[CH:8]=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:12]=[C:11]([CH:33]3[CH2:32][CH2:3][CH2:2][CH2:1][CH2:6]3)[CH2:10]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1.[Na+:31]
Reactant: CCO
Reactant: c1cc(C2CCCCC2)c(C2CCCCC2)c(C2CCCCC2)c1
Reactant: O=S(=O)(O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)([O-])C1(C2CCCCC2)C=C(C2CCCCC2)C=C(C2CCCCC2)C1
Temperature: 3 °C

Procedure:
Subsequently, 30 g of tricyclohexylbenzene was dissolved in 50 ml of methylene chloride, and the solution was stirred under cooling at 3° C. Thereto, 15.2 g of chlorosulfonic acid was slowly added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 5 hours, charged with 10 g of ice and then charged with 40 g of an aqueous 50% sodium hydroxide solution. furthermore, 20 g of ethanol was added, and the mixture was stirred at 50° C. for 1 hour. Insoluble matters were removed by filtration, and the residue was distilled at 40° C. under reduced pressure. The precipitated crystal was collected by filtration and washed with hexane to obtain 30 g of sodium 1,3,5-tricyclohexylbenzenesulfonate.