Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]4=[O:29])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:37][CH2:38][OH:39]>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:37][CH2:38][OH:39])[C:23]4=[O:29])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=C(NCc1cn(-c2ccc(-n3cccc(O)c3=O)cc2)nn1)c1ccc(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3cccc(OCCO)c3=O)cc2)nn1)c1ccc(Cl)s1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-N-((1-(4-(3-hydroxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (30 mg, 0.07 mmol, prepared as shown in EXAMPLE 61) was dissolved in 2 mL DMSO. To it were added cesium carbonate (69 mg, 0.21 mmol) and 2-bromoethanol (10 μL, 0.14 mmol). The mixture was stirred in a sealed tube at 70° C. for 30 min, and was directly subjected to reverse phase prep HPLC to isolate the title compound. MS found for C21H18ClN5O4S (M+H)+ 472.1, 474.1 (Cl pattern).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:11][CH2:10][Br:9]
Reactant: Oc1ccccc1Br
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: BrCCOc1ccccc1Br
Temperature: 80 °C

Procedure:
A suspension of 2-bromophenol (3.50 g, 20.23 mmol), 1,2-dibromoethane (19.00 g, 101 mmol), and potassium carbonate (7.06 g, 2.92 mmol) in acetonitrile (50 mL) was heated to 80° C. After heating overnight, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to afford the title compound as a clear oil. Yield: 6.36 g, 100%. 1H NMR (400 MHz, CDCl3) δ 3.69 (dd, J=6.6, 6.4 Hz, 2H), 4.35 (dd, J=6.7, 6.4 Hz, 2H), 6.87-6.94 (m, 2H), 7.25-7.30 (m, 1H), 7.56 (dd, J=7.9, 1.6 Hz, 1H).
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH2:4]([S:12][CH2:13][CH2:14][NH2:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(#N)C>[C:1](=[O:3])([OH:2])[NH2:15].[CH2:4]([S:12][CH2:13][CH2:14][NH2:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C=O
Agent: CCCCCCCCSCCN
Solvent: CC#N
Product: NC(=O)O

Procedure:
Carbon dioxide is bubbled through an acetonitrile (60 ml) solution of 10 g (52.8 mmoles) of 2-(octylthio)ethylamine to afford a white precipitate which is isolated by suction filtration. The product is washed three times with 10 ml portions of acetonitrile and is then washed three times with 20 mls portions of methyl t-butyl ether. The product is air dried to give 7.77 g of octylthioethylamine carbamic acid derivative as a white powder (yield, 62.1%). The product is further characterized by IR, proton NMR, and elemental analysis.
Reaction SMILES: [NH2:1][C:2]([CH2:23][OH:24])([CH2:21][CH3:22])[CH2:3][S:4]([C:7]1[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)(=[O:6])=[O:5].Cl>N1C(C)=CC=CC=1C.C(OCC)C>[CH2:21]([C:2]1([CH2:23][OH:24])[N:1]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=2[S:4](=[O:6])(=[O:5])[CH2:3]1)[CH3:22]
Reactant: CCC(N)(CO)CS(=O)(=O)c1ccccc1C(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1cccc(C)n1
Product: CCC1(CO)CS(=O)(=O)c2ccccc2C(c2ccccc2)=N1
Yield: 70 %

Procedure:
The product from step (b) (38.7 g) was dissolved in 600 ml of 2,6-lutidine and 120 ml of 1.0M HCl in diethyl ether was then added. The reaction mixture was refluxed overnite, using a Dean Stark trap, then concentrated in vacuo. The residue was taken up in 5% NaHCO3 whereupon solidification took place. The solids were filtered and washed with ether to afford the desired product as a light brown solid (25.7 g), mp 170°-171° C. 1H NMR consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][CH2:10][CH2:11][Cl:12].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:9][CH2:10][CH2:11][Cl:12])=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: ClCCCSc1ccccc1Br
Product: O=S(CCCCl)c1ccccc1Br

Procedure:
Prepared by Procedure S and Scheme AA using 1-bromo-2-[(3-chloropropyl)sulfanyl]benzene and 1 eq m-CPBA: ESMS m/e: 282.8 (M+H)+.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8](/[C:11](/[C:15]3[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=3)=[CH:12]/[CH2:13][OH:14])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.O[C:23]1[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH:1]1([S:4][C:5]2[CH:6]=[CH:7][C:8](/[C:11](/[C:15]3[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=3)=[CH:12]/[CH2:13][O:14][C:23]3[CH:34]=[CH:33][C:26]([O:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[C:25]([CH3:35])[CH:24]=3)=[CH:9][CH:10]=2)[CH2:2][CH2:3]1
Reactant: OC/C=C(\c1ccc(I)cc1)c1ccc(SC2CC2)cc1
Reactant: COC(=O)COc1ccc(O)cc1C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(SC3CC3)cc2)cc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The above allyl alcohol (3.40 g, 8.30 mmol), methyl (4-hydroxy-2-methylphenoxy)-acetate (1.79 g, 9.13 mmol; compound VÚFB-21004) and triphenylphosphine (2.5 g, 9.55 mmol) were dissolved in a mixture of anhydrous toluene (38 mL) and tetrahydrofuran (13 mL). The mixture was cooled to 0° C., kept under nitrogen and a degassed solution of diisopropyl azodicarboxylate (1.88 mL, 9.55 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and then was stirred overnight. The solvents were evaporated in vacuo and the residue was submitted to flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 10:1-8:1) affording methyl (Z)-[4-[3-(4-cyclopropylsulfanylphenyl)-3-(4-iodophenyl)allyloxy]-2-methyl-phenoxy]acetate as yellowish oil.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:24]=[O:25].O>O1CCCC1.C(OCC)(=O)C>[CH3:14][C:10]1[N:9]=[C:8]([O:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1cccc(OCc2ccc(Br)cc2)n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(OCc2ccc(C=O)cc2)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a solution of 2-(4-bromo-benzyloxy)-6-methyl-pyridine (7.30 g, 26.2 mmol) described in Manufacturing Example 3-1-1 in anhydrous tetrahydrofuran (200 mL) was added dropwise n-butyl lithium (2.67 M n-hexane solution, 11.8 mL, 31.4 mmol) on a dry ice-ethanol bath (−78° C.), which was stirred for 30 minutes at −78° C. N,N-dimethylformamide (4.04 mL, 52.4 mmol) was added to this mixture at −78° C., and stirred for 5 minutes. Water and ethyl acetate were added to the reaction mixture, which was stirred for 10 minutes at room temperature, and the organic layer was then separated. This organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (4.19 g, 70%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][C@H:17]([CH3:19])[CH2:16][CH2:15][C@H:14]2[CH:20]([CH3:22])[CH3:21])=[O:12])=[CH:6][CH:5]=1)#[N:2].C([C@@H]1CC[C@@H](C)C[C@@H]1C(N)=O)(C)C.C(CC1C=CC(I)=CC=1)#N>>[C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[CH2:18][C@H:17]([CH3:19])[CH2:16][CH2:15][C@H:14]2[CH:20]([CH3:22])[CH3:21])=[O:12])=[CH:6][CH:5]=1)#[N:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(=O)Nc1ccc(CC#N)cc1
Agent: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C(N)=O
Agent: N#CCc1ccc(I)cc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1C(=O)Nc1ccc(CC#N)cc1

Procedure:
N-[4-(cyanomethyl)phenyl]-(1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide was prepared as described above for the preparation of the N-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide isomer, i.e., by coupling the (1S,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide prepared in steps A to C above with 4-(cyanomethyl)phenyl iodide. The (1S,2S,5R)-material (neoisomer) has the following properties with structure confirmed by obtaining an X-ray crystal structure of a sample crystallized from hexane/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([CH2:14]S([O-])(=O)=O)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:19][CH2:20][C@@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[OH:22].C(NCCCC)CCC.[OH-].[Na+]>>[Cl:29][C:25]1[CH:24]=[C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH:12]([CH3:14])[CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Reactant: COc1ccc(C[C@H](C)CS(=O)(=O)[O-])cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCNCCCC
Product: COc1ccc(CC(C)NCC(O)c2cccc(Cl)c2)cc1OC
Temperature: 60 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
To 274 mg (1.00 mmol) of (S)-[2-(3,4-dimethoxyphenyl)-1-methylethyl methanesulfonate] were added 206 mg (1.20 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol and 194 mg (1.50 mmol) of dibutylamine, and the mixture was stirred at 60° C. for 24 hours under nitrogen atmosphere. The reaction mixture was added with a 10% aqueous solution of sodium hydroxide to be alkaline, and extracted twice with 30 ml of toluene. The toluene extract was dried over anhydrous sodium sulfate, and subjected to distillation of the solvent and to purification with silica gel chromatography to give 190 mg of 1-(3-chlorophenyl)-2-[[2-(3,4-dimethoxyphenyl)-1-methylethyl]amino]ethanol as white crystals (yield: 54%). As a result of isolating and analyzing the isomers by high performance liquid chromatography using an optical resolution column (column: Chiralpack AD (trade name), Daicel Chemical Industries, Ltd.), the optical purity of the objective compound was 95.2% [(R,R)/(R,S)=95.2/4.8].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[CH3:17][N:18]=[C:19]=[O:20]>C(N(CC)CC)C.ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[N:12]([C:19](=[O:20])[NH:18][CH3:17])[C:11]1=[O:16]
Reactant: CN=C=O
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CNC(=O)N1C(=O)OC(c2c(Cl)cccc2OC)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-(2-Chloro-6-methoxyphenyl)oxazolidin-2,4-dione (1.21 g., 5 mmoles) was suspended in 25 ml. of 1,2-dichloroethane. Triethylamine (1 drop) and then methyl isocyanate (285 mg., 0.29 ml., 5 mmoles) were added and the mixture stirred for 3 hours at room temperature, by which time solution had resulted. The reaction mixture was diluted with 50 ml. of 1,2-dichloroethane, washed with two portions of saturated sodium bicarbonate and then with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to product. Recrystallization from chloroform-hexane afforded purified 5-(2-chloro-6-methoxyphenyl)-3-methylcarbamoyloxazolidin-2,4-dione [1.04 g., 70%; m.p. 124°-127° C. (dec); m/e 300/298].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:26][CH2:24][CH3:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC1C(C(=O)OCC)=C(c2ccccc2)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.27 mmol) obtained in Example 18 was dissolved in THF (10 mL), and 2.0 M ethylamine (0.68 mL, 1.35 mmol) in THF was added dropwise thereto. The mixture was stirred for 12 hrs at RT, and the solvent was removed under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 68 mg of the titled compound (yield: 75.6%).
Reaction SMILES: [F:1][C:2]([F:17])([C:5]([F:16])([F:15])[O:6][C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10])[C:3]#[N:4].[O:18]=O>>[F:1][C:2]([F:17])([C:5]([F:15])([F:16])[O:6][C:7]([F:14])([F:13])[C:8]1([F:12])[O:18][C:9]1([F:11])[F:10])[C:3]#[N:4]
Reactant: N#CC(F)(F)C(F)(F)OC(F)(F)C(F)=C(F)F
Reactant: O=O
Product: N#CC(F)(F)C(F)(F)OC(F)(F)C1(F)OC1(F)F

Procedure:
A 100-ml stainless steel-lined tube charged with 38.5 g (0.14 mol) of perfluoro-4-oxa-6-heptenenitrile was heated at 140° while oxygen was added incrementally (over 5.5 h) until reaction was complete. Fractionation of the liquid products gave perfluoro-6,7-epoxy-4-oxaheptanenitrile, bp 65°-67°, 15.7 g (39%). IR (CCl4); 4.40 (CN), 6.47 (epoxide) and 8-9μ (CF, C-O). NMR (CCl4): -87.5 (m, 2F, OCF2), -109.2 (t, JFF 4.7 Hz, 2F, CF2CN), and -156.7 ppm (d of d of m, JFF 18.7, 16.7 Hz, 1F, CF) with AB groupings for ring CF2 at -10347 and -10389 Hz (d of t, JFF 18.7, 9.5 Hz, 1F) and -10570 and -10610 Hz (d, JFF 16.7 Hz, 1F) and for CF 2 adjacent to epoxide ring at -7376, -7529, -7556, and -7707 Hz (m, 2F).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[C:10]([CH2:13][OH:14])[NH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1COCC1.O=[Mn]=O>[N:1]1([CH2:6][CH2:7][C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[NH:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCc1cc(CCN2CCCC2)c[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: O=Cc1cc(CCN2CCCC2)c[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the product obtained in Step I (0.09 g) in THF (3.8 ml) there is added activated MnO2 (0.315 g). After stirring for 20 hours at ambient temperature, the mixture is filtered and the filtrate is evaporated to dryness to yield the title product, which is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:24][CH3:25])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][C:17]([CH3:22])([CH3:21])[C:16]2=[O:23])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.C=O.[CH2:28](N(CC)CC)C>CO>[CH3:1][O:2][CH:3]([O:24][CH3:25])[C:4]1[C:13]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:28])[C:17]([CH3:22])([CH3:21])[C:16]2=[O:23])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: CCN(CC)CC
Reactant: COC(OC)c1nc2c(cc1CN1CCNC(C)(C)C1=O)CCCN2
Agent: C=O
Solvent: CO
Product: COC(OC)c1nc2c(cc1CN1CCN(C)C(C)(C)C1=O)CCCN2
Temperature: 25 °C
Reaction time: 528 h

Procedure:
A mixture of 1-((2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl)-3,3-dimethylpiperazin-2-one (intermediate 304, 100 mg, 0.287 mmol), formaldehyde (36.5% in water, 22 μl, 0.290 mmol) and triethylamine (100 μl, 0.721 mmol) in MeOH (2 ml) was stirred at room temperature for 22 days before being partitioned between aqueous saturated NaHCO3 and DCM, extracting 2× with DCM, the combined organic layers dried over Na2SO4 and evaporated. The crude material was preabsorbed onto isolate and purified by normal phase chromatography: 4 g RediSep column, eluting with a gradient from DCM to 95:5 DCM:MeOH containing 1% NH3. The product containing fractions were combined and evaporated to give the title compound as a colourless glass. 1H NMR (400 MHz, CDCl3) δ 7.03 (s, 1H), 5.21 (s, 1H), 4.65 (s, 2H), 3.42-3.35 (m, 8H), 3.20-3.13 (m, 2H), 2.72 (t, 2H), 2.67 (t, 2H), 2.33 (s, 3H), 1.87 (m, 2H), 1.36 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([OH:14])=O)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:19][S:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([NH:29][NH2:30])=[O:28])=[CH:25][CH:24]=1)(=[O:22])=[O:21]>>[Cl:1][C:2]1[C:3]([CH3:18])=[C:4]([NH:10][C@H:11]([C@@H:15]([OH:17])[CH3:16])[C:12]([N:29]([C:27](=[O:28])[C:26]2[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:32][CH:31]=2)[NH2:30])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Product: Cc1c(N[C@@H](C(=O)N(N)C(=O)c2ccc(S(C)(=O)=O)cc2)[C@H](C)O)ccc(C#N)c1Cl
Yield: 83.2 %

Procedure:
(2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (813 mg, 3.0 mmol) and 4-(methylsulfonyl)benzohydrazide (648 mg, 3.0 mmol) were coupled in a procedure analogous to that described for the preparation of intermediate 3b. The crude product was recrystallized from hotchloroform (100 mL to yield product as a white solid (1.16 g, 82%). 1H NMR (500 MHz, acetone-d6, δ in ppm) 9.83 (br s, 2H), 8.14 (AA′XX′, J=8.5 Hz, 2H), 8.06 (AA′XX′, J=8.5 Hz, 2H), 7.53 (d, J=8.6 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 5.57 (d, J=7.0 Hz, 1H), 4.40 (m, 1H), 4.14 (dd, J=3.4, 6.9 Hz, 1H), 3.19 (s, 3H), 2.90 (br s, 1H), 2.36 (s, 3H), 1.36 (d, J=6.4 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]2[N:13]=[C:14]([NH:17][C:18]([NH2:20])=[NH:19])[S:15][CH:16]=2)=[N:5]S(=O)[N:3]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[ClH:22].[NH:17]([C:14]1[S:15][CH:16]=[C:12]([CH2:11][S:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[N:13]=1)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)Nc1nc(CSCCNC2=NS(=O)N=C2N)cs1
Agent: Cl
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNC(=N)C(=N)N)cs1
Temperature: 25 °C
Reaction time: 4.25 h

Procedure:
A suspension of 3-amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole 1-oxide (5.25 g; 13.7 mmoles) [prepared according to published United Kingdom patent application No. 2,067,987] in 105 ml of methanol was treated with 80 ml of concentrated HCl to give an immediate yellow solution. After stirring at ambient temperature for 4.25 hours, the solution was concentrated to near dryness and the residue was triturated with acetone, filtered and dried to give the title compound.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][CH:18]=1)O)C1C=CC=CC=1.Cl>[Pd].CO>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:18][CH:19]=1)[CH3:24]
Reactant: CCc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc(Cc2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 108.5 %

Procedure:
Then a mixture of (2-benzyloxyphenyl)(4-ethylphenyl)methanol (78.5 g), 10% palladium activated carbon (5.2 g), concentrated hydrochloric acid (10.4 mL) and methanol (850 mL) was stirred under hydrogen atmosphere at room temperature for 24 hours. After filtering off the insolubles, the filtrate was evaporated under reduced pressure and then, the residue was distilled under reduced pressure to obtain the title compound (56.8 g) as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:20])=O>>[O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Product: O=C(Cl)c1ccc(Oc2ccccc2)cc1

Procedure:
4-Phenoxybenzoyl chloride was prepared by reacting 4-phenoxybenzoic acid with oxalyl chloride.
Reaction SMILES: C([O:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][C:10]=1[F:26])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:25]=[CH:24][C:12]([C:13]([O:15][C@H:16]([CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:14])=[CH:11][C:10]=1[F:26]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(O)c(F)c1
Reaction time: 24 h

Procedure:
10% Palladium on charcoal (0.3 g), was added to a solution of compound 12 (10.0 g, 28 mmol) in ethyl acetate (300 ml). The solution was evacuated and left stirring with hydrogen at atmospheric pressure for 24 h. The catalyst was filtered off and the solvent removed in vacuo to yield a yellow oil which was purified by column chromatography (dichloromethane) on silica to yield the pure colourless oil. Yield 5.8 g (77%). [α]D=−33.7° at 25° C.
Reaction SMILES: C1S[C:4]2([C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=3)[CH2:6][CH:5]2[NH:15][C:16]([O:18][CH3:19])=[O:17])SC1>[Ni].C(O)C>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH2:6][CH:5]([NH:15][C:16]([O:18][CH3:19])=[O:17])[CH2:4]2
Reactant: COC(=O)NC1Cc2ccc(OC)cc2C12SCCS2
Agent: [Ni]
Solvent: CCO
Product: COC(=O)NC1Cc2ccc(OC)cc2C1
Yield: 93.8 %

Procedure:
A mixture of 6-methoxy-2-(methoxycarbonylamino)indan-1-one ethylene dithioacetal (0.12 g), Raney nickel (suspension in water; 5 ml), and ethanol (12 ml) was refluxed for 0.5 hour. The mixture was filtered and the catalyst was washed with hot ethanol. The filtrate and washings were combined and concentrated in vacuo. Purification of the residue by column chromatography on silica gel (eluent; chloroform) gave 5-methoxy-N-methoxycarbonylindan-2-amine (0.08 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.Cl[Pd-](P(C1CC2CC1CC2)C1CC2CC1CC2)[C-]1C=CC=C1N(C)C.[CH-]1C=CC=C1.[Fe+2]>[CH:9]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[N:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Fc1ccc(Br)cn1
Reactant: OB(O)C1CC1
Agent: CN(C)c1ccc[c-]1[Pd-](Cl)P(C1CC2CCC1C2)C1CC2CCC1C2
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Fc1ccc(C2CC2)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoro-5-bromopyridine (1.17 ml, 11.4 mmol), cyclopropylboronic acid (1.47 g, 17.1 mmol) and potassium phosphate (7.26 g, 34.2 mmol) in 1,4-dioxane (20 ml) was stirred under argon atmosphere. Chloro(di-2-norbornylphosphino)(2-dimethylaminoferrocen-1-yl)palladium(II) (67 mg, 0.11 mmol) was added. The reaction mixture was heated at 100° C. under argon atmosphere for 48 hours and then cooled down to room temperature. The crude mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion|, 80 g column, 0-10% EtOAc/Petroleum ether) to afford the compound (70:30 mixture product: starting material; 1.55 g).