Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([O:26][C:27](=O)[C:22]=12)=[O:25]>ClCCl>[Cl:20][C:21]1[CH:31]=[CH:30][C:29]([Cl:32])=[C:23]2[C:24]([N:1]([C:2]3[C:7]4[O:8][C:9]([CH3:12])=[C:10]([CH3:11])[C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:27](=[O:26])[C:22]=12)=[O:25]
Reactant: Cc1oc2c(N)cccc2c1C
Reactant: O=C1OC(=O)c2c(Cl)ccc(Cl)c21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1oc2c(N3C(=O)c4c(Cl)ccc(Cl)c4C3=O)cccc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
A mixture of 7-amino-2,3-dimethylbenzo[b]furan (161 mg), triethylamine (202 mg) and 3,6-dichlorophthalic anhydride (261 mg) in dichloromethane (5 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was washed with 1N-hydrochloric acid and brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved in methanol and treated with diazomethane. The separated solid was collected and washed with methanol to give 7-(3,6-dichlorophthalimido)-2,3-dimethylbenzo[b]furan (250 mg).
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH2:22]([C@H:24]1[CH2:32][C:31]2[C:26](=[CH:27][C:28]([O:33][CH3:34])=[CH:29][CH:30]=2)[C@H:25]1[NH2:35])[CH3:23]>>[CH2:1]([C:3]1[C:4]([NH:35][C@@H:25]2[C:26]3[C:31](=[CH:30][CH:29]=[C:28]([O:33][CH3:34])[CH:27]=3)[CH2:32][C@@H:24]2[CH2:22][CH3:23])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CC[C@H]1Cc2ccc(OC)cc2[C@H]1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCc1cnc(CC)c(N[C@@H]2c3cc(OC)ccc3C[C@@H]2CC)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting cis-2-ethyl-6-methoxy-2,3-dihydro-1H-inden-1-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 0.93, 1.27-1.34, 2.58, 2.68, 3.00, 3.79, 4.44, 5.83, 6.80, 6.92, 7.17, 7.68; HRMS (EI) calcd for C20H27N3O 325.2154, found 325.2157.
Reaction SMILES: [Li].[Na].N.[C:4]1(OC=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O=[CH:14]C(Cl)(Cl)Cl.[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>C(OC=O)C.CCOC(C)=O.C1COCC1>[CH2:14]([CH:19]1[C:28]2[CH:23]([CH2:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=COc1ccccc1
Agent: N
Agent: [Li]
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOC=O
Product: C1=CCC2CCNC(Cc3ccccc3)C2=C1

Procedure:
Birch reduction with lithium or sodium in liquid ammonia of 85 mmol of unpurified 7 with 1.92 g atom of lithium in 450 ml of liquid NH3, 225 ml each of dry THF and 6-BuOH at -55° to -65° C. for 4 hrs., then at -75° C. until no 7 remained by TLC (~1.5 h) afforded (90%) essentially pure (TLC) 8, mp 179.5° C. Refluxing unpurified 8 with 1.5 equivalents of pure PhOCHO, chloral in 10 volumes of EtOAc or in EtOCHO until TLC showed absence of 8 gave (94%) pure 10, which, as the N-formyl derivatives described below and others, existed as two distinct rotomers, as shown by NMR. This N-formyl derivatization introduces a protective group for the nitrogen in the subsequent steps of the reaction. Compound 7 or 8 may be N-methylated with methyl halide or sulfonate to give compound 9. Stirring a solution of 10 (25° C., 1 h.) in 20 volumes of dry THF containing 1% (v/v) CH3SO3H and 3 molar equivalents of ethylene glycol generated a solution of ketal 11 (quantitatively by TLC) which was treated at 0°-5° C. during 0.5 h with 1.05 equivalents of recrystallized N-bromoacetamide (NBA) to afford essentially pure bromoketal 12 after neutralization with NH3 gas, solvent evaporation and workup with CHCl3 --H2O. Bromoketal 12 was most efficiently deketalized in 6 volumes of 5:1 88% HCO2H--H2O (25° C., 1 h) followed by CHCl3 -aqueous NaHCO3 workup to afford 13, IR (CHCl3) 1717 (C=O) and 1665 (NCHO) cm-1 in 90% yield from 10.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][C@H:8]([CH3:17])[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10]
Reactant: C1=COCCC1
Reactant: C[C@@H](O)C(=O)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](OC1CCCCO1)C(=O)N1CCOCC1
Temperature: 0 °C
Yield: 95 %

Procedure:
3,4-Dihydro-2H-pyran (90.5 ml, 1.2 eq) was added dropwise to a mixture of 4-[(R)-2-hydroxypropionyl]morpholine (132 g) and p-toluenesulfonic acid monohydrate (500 mg, 0.003 eq) in dry dichloromethane (500 ml) over a period of 15 min with stirring at 0° C. After being stirred for 30 min at 0° C., the mixture was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, using n-hexane: ethyl acetate (8:1)˜ethyl acetate as an eluent, gave 4-[(2R)-2-(3,4,5,6-Tetrahydro-2H-pyran-2-yloxy)propionyl]morpholine (191.6 g, 95% yield) as a pale yellow oil.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([O:15][CH2:16][O:17][CH3:18])([CH2:13][CH3:14])[CH2:9][CH2:10][C:11]#[CH:12])[CH3:7].[C:19]([O:27][CH:28]1[CH2:36][CH2:35][CH2:34][C:33]2([CH3:37])[CH:29]1[CH2:30][CH2:31][CH:32]2[C:38](=[O:40])[CH3:39])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:19]([O:27][CH:28]1[CH2:36][CH2:35][CH2:34][C:33]2([CH3:37])[CH:29]1[CH2:30][CH2:31][CH:32]2[C:38]([OH:40])([C:12]#[C:11][CH2:10][CH2:9][C:8]([CH2:13][CH3:14])([O:15][CH2:16][O:17][CH3:18])[CH2:6][CH3:7])[CH3:39])(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(=O)C1CCC2C(OC(=O)c3ccccc3)CCCC12C
Reactant: C#CCCC(CC)(CC)OCOC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCC(CC)(CCC#CC(C)(O)C1CCC2C(OC(=O)c3ccccc3)CCCC21C)OCOC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
0.32 ml of 1.6M hexane solution of butyl lithium was dropwise added to a solution of 120 mg of 5-ethyl-5-methoxymethoxy-1-heptyne dissolved in 4 ml of tetrahydrofuran, at -78° C. in a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 minutes. Thereto was dropwise added a solution of 112 mg of 4-benzoyloxy-7a-methyl-2,3,3a,4,5,6,7,7a-octahydroinden-1-yl-ethanone dissolved in 3 ml of tetrahydrofuran. The reaction mixture was warmed to 0° C. and mixed with an aqueous ammonium chloride solution. The mixture was subjected to extraction with diethyl ether. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 97 mg of 2-(4-benzoyloxy-7a-methyl-2,3,3a,4,5,6,7,7a-octahydroinden-1-yl)-7-ethyl-7-methoxymethoxy-3-nonyn-2-ol having the following properties.
Reaction SMILES: [NH3:1].[Cl:2][Ge:3]([Cl:11])([Cl:10])[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7]>C(Cl)(Cl)Cl>[Cl:2][Ge:3]([Cl:11])([Cl:10])[CH2:4][CH2:5][S:6]([NH2:1])(=[O:8])=[O:7]
Reactant: N
Reactant: O=S(=O)(Cl)CC[Ge](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)CC[Ge](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To chloroform solution (16.0 ml) saturated with ammonia, 2-trichlorogermylethanesulfonylchloride (500 mg, obtained by Example 7) in chloroform solution (2.0 ml) was added dropwise and stirred for 22 hours at room temperature.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[C:4]([C:14]2[CH:15]=[C:16](O)[CH:17]=[CH:18][CH:19]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:32])[C:29]([CH3:31])=[CH2:30].[OH2:34]>C(Cl)Cl>[C:28]([O:32][C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:4]1[C:5]2[S:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=[CH:2][CH:3]=1)(=[O:34])[C:29]([CH3:31])=[CH2:30]
Reactant: C=C(C)C(=O)Cl
Reactant: O
Reactant: Oc1cccc(-c2cccc3c2sc2ccccc23)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)Oc1ccccc1-c1cccc2c1sc1ccccc12
Reaction time: 0.5 h
Yield: 78 %

Procedure:
0.65 g of 3-(4-dibenzothiophenyl)phenol obtained in Synthesis Example 5-(i) is placed and dissolved in 20 mL of methylene chloride; after ice cooling the flask, 0.28 g of triethylamine is added; 0.29 g of methacryloyl chloride is then added dropwise; after adding the whole, the temperature is returned to room temperature; and the mixture is stirred for 30 minutes. 10 mL of water is added; the mixture is vigorously stirred; an aqueous layer is then removed; the aqueous layer is washed with methylene chloride and then gathered with the original methylene chloride solution; and the mixture is dried upon application of magnesium sulfate. The resulting mixture is concentrated by filtration with a filter paper; and the concentrate is separated by a silica gel column (eluate: hexane/ethyl acetate=80/10 (volume ratio)) to concentrate a component having an Rf of 0.50, thereby obtaining 0.63 g (yield: 78%) of the foregoing white solid. 1H NMR (CDCl3, 400 MHz): δ (ppm) 2.09 (s, 3H), 5.77 (dd=1.6 Hz, 1H), 6.39 (s, 1H), 7.21 (m, 1H), 7.45 to 7.55 (m, 6H), 7.62 to 7.64 (m, 1H), 7.82 to 7.85 (m, 1H), 8.14 to 8.19 (m, 2H)
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.[C:29]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30]>O1CCCC1>[Si:33]([O:10][CH2:9][C:5]1[C:4]([O:11][CH3:12])=[CH:3][C:2]([NH2:1])=[C:7]([F:8])[CH:6]=1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(N)c(F)cc1CO
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N)c(F)cc1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (4-amino-5-fluoro-2-methoxyphenyl)methanol (intermediate 91; 1.49 g, 8.7 mmol) in tetrahydrofuran (117 mL) was added dimethylaminopiridine (0.1 g, 0.81 mmol) and triethylamine (3.4 mL, 24.3 mmol). Then the mixture was cooled to 0° C. and tert-butylchlorodimethylsilane (2.45 g, 16.2 mmol) was added under argon atmosphere. The mixture was stirred 2 hours at room temperature. The solvent was removed under reduced pressure and the crude obtained was purified by column chromatography with silica gel, eluting with hexane/ether (from 0% to 100%). The title compound was obtained as an pale-orange solid (82%).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:21][CH:17]4[CH2:18][CH:19]([CH2:20]2)[C:15]([NH2:22])([CH2:16]4)[CH2:14]3)=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:31][C:32]([N:34]1[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]1[C:40]#[N:41])=[O:33]>CS(C)=O.CCOC(C)=O>[O:1]=[S:2]1(=[O:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]23[CH2:21][CH:17]4[CH2:16][C:15]([NH:22][CH2:31][C:32]([N:34]5[CH2:38][C@@H:37]([F:39])[CH2:36][C@H:35]5[C:40]#[N:41])=[O:33])([CH2:14]2)[CH:19]([CH2:18]4)[CH2:20]3)=[CH:11][CH:12]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CCl
Reactant: NC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CC3CC1CC(c1ccc(N4CCCS4(=O)=O)cc1)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 37 %

Procedure:
To a stirred mixture of 1-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]tricyclo[3.3.1.03,7]nonan-3-amine (as obtained in example 8 Step II) (0.17 g, 0.5 mmol) and K2CO3 (0.21 g, 1.5 mmol) in DMSO (2 mL) at an ice bath temperature was added (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile (0.1 g, 0.5 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S,4S)-1-{N-[2-[4-(1,1-dioxidoisothiazolidin-2-yl)phenyl]hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}-4-fluoropyrrolidine-2-carbonitrile as an off-white powder (0.09 g) in 37% yield as a 3:1 mixture of two rotomers. IR cm−1 3438, 2953, 2776, 1673, 1518, 1427, 1301, 1135, 1078, 955; m/z (M+1) 487; 1H NMR (CDCl3) 300 MHz δ 7.25 (d, J=6.2 Hz, 2H), 7.20 (d, J=8.6 Hz, 2H), 5.42 (d (br), J=51.0 Hz, 0.8H), 5.34 (d (br), J=50.4 Hz, 0.2H), 5.15 (d, J=10.2 Hz, 0.2H), 4.98 (d, J=7.4 Hz, 0.8H), 4.0-3.50 (m, 4H), 3.76 (t, J=6.5H, 2H), 3.35 (t, J=6.5 Hz, 2H), 2.80-2.28 (m, 6H), 2.15-1.58 (m, 10H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([S:11]([F:14])(=[O:13])=[O:12])=[CH:5][C:6]=1[S:7]([F:10])(=[O:9])=[O:8].C1N2CN3CN(C2)C[N:16]1C3.S(=O)(=O)(O)O>CO>[NH2:16][C:2]1[S:3][C:4]([S:11]([F:14])(=[O:13])=[O:12])=[CH:5][C:6]=1[S:7]([F:10])(=[O:9])=[O:8]
Reactant: O=S(=O)(F)c1cc(S(=O)(=O)F)c(Cl)s1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1sc(S(=O)(=O)F)cc1S(=O)(=O)F
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of 2-chloro-3,5-bisfluorosulphonylthiophene (8.5 g), hexamine (8.5 g) and methanol (90 ml) was stirred under reflux for one hour. The mixture was cooled to 25° C., poured into dilute sulphuric acid and extracted with ethyl acetate to give the product as an oil (6.3 g).
Reaction SMILES: [ClH:1].Cl[C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10](C)[CH2:9]2)=[CH:5][CH:4]=1.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C([O-])([O-])=O.[K+].[K+]>C1C=CC=CC=1>[Cl:1][C:19]1[CH:20]=[CH:3][CH:4]=[CH:5][C:6]=1[O:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1
Reactant: Cl
Reactant: CN1Cc2ccccc2C(Oc2ccc(Cl)cc2)C1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1Cc2ccccc2C(Oc2ccccc2Cl)C1

Procedure:
A mixture of 4-(p-chlorophenoxy)-2-methyl-1,2,3,4-tetrahydroisoquinoline of Example 7, (22.1 g, 0.08 mole), ethyl chloroformate (10.9 g, 0.1 mole) and K2CO3 (22 g) in benzene (250 ml) is refluxed seven hours.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:12][C:13]1[C:14]([F:30])=[CH:15][C:16]2[N:20]=[C:19]([S:21][C:22]3[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=3)[NH:18][C:17]=2[CH:29]=1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][C:33](=[O:37])[CH2:32]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:27]([C:25]3[O:26][C:22]([S:21][C:19]4[NH:18][C:17]5[CH:29]=[C:13]([Cl:12])[C:14]([F:30])=[CH:15][C:16]=5[N:20]=4)=[CH:23][CH:24]=3)[C:32]3[C:33](=[O:37])[CH2:34][CH2:35][CH2:36][C:31]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1ccc(Sc2nc3cc(F)c(Cl)cc3[nH]2)o1
Reactant: O=C1CCCC(=O)C1
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(F)c(Cl)cc3[nH]2)o1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.192 g, 1.25 mmol), 5-(6-chloro-5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.37 g, 1.25 mmol) and 1,3-cyclohexanedione (0.14 g, 1.25 mmol) in 5 ml of 1-butanol is heated at reflux temperature for 2 hours. The reaction mixture is then concentrated under reduced pressure. The residue is resuspended in 5 ml of acetonitrile and the mixture is heated at reflux temperature for 30 minutes. The mixture is allowed to cool to room temperature and the insoluble material is collected by filtration, washed with diisopropylether (20 ml), pentane (20 ml) and dried under vacuum to yield 363 mg of 9-[5-(6-chloro-5-fluoro-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-8-oxo-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a white powder. Yield=55%. Analytical LC/MS (method B): m/z=525 (negative ion mode, [M−H]−, 1 Cl present), m/z=527 (positive ion mode, [M+H]+, 1 Cl present).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]2)[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(c2nc(Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a suspension of 2,4,6-trichloro-1,3,5-triazine (5.0 g, 27 mmol, 1.0 equiv) in dichloromethane (50 ml) at −50° C., a premixed solution of ethyl 4-piperidinecarboxylate (4.1 ml, 27 mmol, 1.0 equiv) and diisopropylethylamine (DIEA, 14.2 ml, 81.3 mmol, 3.00 equiv) in dichloromethane (100 ml) was added dropwise via an addition funnel. The reaction mixture was allowed to warm to room temperature, and stirring was continued overnight. The solvent was removed under reduced pressure to yield 7.95 g (96%) of the title compound. MS (ES+): m/e 305.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:13][CH:12]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2ccc(C(F)(F)F)cc2)CC1

Procedure:
Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.), 4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.).
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH3:10])[CH:8]=1)([O-])=O.[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[CH2:28][CH:27]([NH:33][CH:34]([CH2:38][CH2:39][CH3:40])[C:35](O)=[O:36])[CH2:26][CH2:25]2>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([CH:9]([N:7]2[CH:8]=[C:4]([NH:1][C:35](=[O:36])[C@@H:34]([NH:33][CH:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:30]([F:32])[CH:31]=[C:22]([F:21])[CH:23]=4)[CH2:28]3)[CH2:38][CH2:39][CH3:40])[N:5]=[CH:6]2)[CH3:10])=[CH:12][CH:13]=1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(c1ccc(C(F)(F)F)cc1)n1cnc([N+](=O)[O-])c1
Product: CCC[C@H](NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)c2ccc(C(F)(F)F)cc2)cn1

Procedure:
4-Nitro-1-[1-(4-trifluoromethyl-phenyl)-ethyl]-1H-imidazole was reduced and then coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) to afford the title compound: MS 521.5 m/z (M+1).
Reaction SMILES: [CH:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2].ClCCCl.[Cl:16][S:17](O)(=[O:19])=[O:18].S(Cl)(Cl)=O>>[CH:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: O=CN1CCc2ccccc21
Solvent: ClCCCl
Solvent: O=S(Cl)Cl
Product: O=CN1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
A 17% (w/w) solution of N-formylindoline in 1,2-dichloroethane (100 g, 680 mmol) was cooled to 5° C., treated with chlorosulfonic acid (90.4 mmol, 1.35 mol) at a rate which kept the internal temperature <25° C., heated to 70° C., treated with thionyl chloride (99.2 mL, 1.35 mol), and stirred for 2 hours. The mixture was cooled to 5° C., quenched with water (1.0 L) at a rate which kept the internal temperature <25° C., warmed to 10° C., diluted with heptane (1.0 L), and stirred for 30 minutes. The resulting precipitate was filtered, washed with water (6×1 L) until the filtrate pH was 4.5, washed with heptane, and partially dried under vacuum at 40° C. to provide the desired product (solid assay for 157 g (94%) of 1-formyl-5-indolinesulfonyl chloride. The product was used directly in the next step without further purification.
Reaction SMILES: [S:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O)[C:2]#[N:3].S(=O)(=O)(O)[OH:18]>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[NH:3][C:2](=[O:18])[S:1][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: N#CSCC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2cccc(C(F)(F)F)c2)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 26.42 g (107.74 mmole) of 2-thiocyanato-1-(3-trifluoromethyl-phenyl)-ethanone, 11 mL of 50% aqueous sulfuric acid and 55 mL of acetic acid was heated at reflux for 1 hour. The mixture was cooled, poured into 500 mL of ice water mixture and stirred for 30 minutes. The solid was collected by filtration, washing with water to give 24 g of 4-(3-trifluoromethyl-phenyl)-3H-thiazol-2-one as a light orange-brown solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](C=CC(OC)=O)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:25]1CCC[CH2:26]1>O.I([O-])(=O)(=O)=O.[Na+].[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:26]=[O:25])=[N:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc(OC)cc12
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COc1ccc2c(c1)c(C=O)nn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester [282 mg, Reference Example 21(a)] in tetrahydrofuran (4 ml) and water (1.5 ml) was treated with a solution of osmium tetroxide in water (54 μL, 4 wt %) and sodium periodate (400 mg). The reaction mixture was stirred at ambient temperature for 16 hours and then filtered. The filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petrol (1:9, v/v) to yield 3-formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester (162 mg) as a white solid. LC-MS (METHOD B): RT=2.97 minutes; 277 (M+H)+.
Reaction SMILES: FC1C=C(N[N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])C=CC=1F.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[F:24])[NH2:20].C(#N)CC#N.O.[NH2:31][NH2:32]>>[F:16][C:17]1[CH:18]=[C:19]([NH:20][N:10]=[C:11]2[C:12]([NH2:13])=[N:32][N:31]=[C:14]2[NH2:15])[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: N#CC(C#N)=NNc1ccc(F)c(F)c1
Reactant: Nc1ccc(F)c(F)c1
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(F)c(F)c1

Procedure:
4-[(3,4-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 103 mg (0.5 mmol) of 2-[(3,4-difluorophenyl)hydrazono]malononitrile, which was derived from 3,4-difluoroaniline (99 μL, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube approximately 5 minutes after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 45 mg (38%) of the compound as a yellow solid; 1H NMR (ppm, DMSO-d6): 6.18 (br s, 4H), 7.28-7.55 (m, 2H), 7.70-7.82 (m, 1H), 10.80 (br s, 1H).