Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[I:13][C:14]1[CH:15]=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH:22]([NH:25][CH2:26][CH2:27][OH:28])[CH2:21][CH2:20]2)[CH:18]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[I:13][C:14]1[CH:15]=[N:16][N:17]([C@H:19]2[CH2:20][CH2:21][C@H:22]([N:25]3[CH2:26][CH2:27][O:28][C:6]3=[O:7])[CH2:23][CH2:24]2)[CH:18]=1
Reactant: OCCNC1CCC(n2cc(I)cn2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C1OCCN1[C@H]1CC[C@H](n2cc(I)cn2)CC1
Temperature: 60 °C

Procedure:
Di-imidazol-1-yl-methanone (1.32 g; 8.14 mmol; 2.9 eq.) was added in one portion to a solution of 2-[4-(4-Iodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 997 mg; 2.83 mmol; 1.0 eq.) and Dimethyl-pyridin-4-yl-amine (60 mg; 0.49 mmol; 0.17 eq.) in CHCl3 (30 mL). The reaction suspension was heated at 60° C. for 20 min then cooled and poured into a 1 N HCl solution. It was extracted with DCM (twice), combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH; 96:4) followed by a trituration in Acetonitrile afforded the title compound as a white solid (239 mg; 23%). 1H NMR (300 MHz, DMSO) δ 7.96 (d, J=0.5 Hz, 1H), 7.51 (d, J=0.5 Hz, 1H), 4.30-4.12 (m, 3H), 3.63-3.46 (m, 3H), 2.11-2.00 (m, 2H), 1.91-1.58 (m, 6H). HPLC (Condition A): Rt 2.98 min (purity 99.0%). MS (ESI+): 362.2.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14]C(=O)CCl)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:14])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1Cc2ccc(OC(=O)CCl)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC1Cc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.6 %

Procedure:
A mixture of 2.5 g of 2-acetylamino-5-chloroacetoxyindan, 50 ml of methanol and 46 ml of an aqueous 1N sodium hydroxide solution is stirred at room temperature for 2.5 hours. The reaction mixture is evaporated to remove methanol and the residual aqueous layer is washed with dimethyl ether, acidified and extracted with ethyl acetate. The extract is washed successively with an aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography and recrystallized from isopropanol-isopropyl ether to give 1.01 g of 2-acetylamino-5-hydroxyindan as colorless needles. Yield: 61%
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[H][H]>[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[CH2:10][CH:9]([CH3:11])[CH:8]([CH3:12])[CH2:7][C:5]=2[N:6]=1
Reactant: [H][H]
Reactant: Cc1nc2cc(C)c(C)cc2[nH]1
Agent: [Pd]
Product: Cc1nc2c([nH]1)CC(C)C(C)C2

Procedure:
10.0 g (62.41 mmol) 2,5,6-Trimethylbenzimidazole are dissolved in 60 ml glacial acid. 2.0 g (1.89 mmol) palladium (10% on carbon) are added under argon and the reaction mixture is treated with hydrogen at a temperature of 150° C. and 80 bar pressure for 48 h. The solution is filtrated over celite and washed with glacial acid. The solvent is evaporated under vacuum, 10 ml water and sodium hydroxid solution are added the solution to a pH of 9-10. The precipitate is filtrated and washed with water. The precipitate is dissolved in ethyl acetate/dichlor-methane and extracted with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtrated and concentrated under vacuum. Diethylether is added, the crystalls are filtrated and dried.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:10]=O.[ClH:12].[CH3:13][NH:14][CH3:15]>>[ClH:12].[CH3:13][N:14]([CH:2]([CH3:10])[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])[CH3:15]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)c1ccccc1
Agent: Cl
Product: CC(C(=O)c1ccccc1)N(C)C
Reaction time: 8 h
Yield: 29 %

Procedure:
A mixture of acetophenone (100 g), paraformaldehyde (25 g) and dimethylamine hydrochloride (68 g) was vigorously stirred and pumped through the CMR (23 ml/min.; 180°-90° C.; 400 kPa). The product tended to crystallise rapidly when cooled, so was collected by passing the hot effluent into a flask which was cooled in ice-water. Analysis by 1H nmr indicated a 44% conversion of acetophenone to product, which was isolated in 29% yield. By conventional methodology8, a crude yield of 71% can be obtained after 2 hours at reflux followed by overnight refrigeration.
Reaction SMILES: [CH3:1][C:2]([C:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH3:18])([CH3:7])[CH2:3][C:4]([OH:6])=O.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:38]=[CH:37][C:31]2[N:32]=[C:33]([C:35]#[N:36])[S:34][C:30]=2[CH:29]=1>C1COCC1>[C:35]([C:33]1[S:34][C:30]2[CH:29]=[C:28]([NH:27][C:4](=[O:6])[CH2:3][C:2]([CH3:1])([C:8]3[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=3[CH3:18])[CH3:7])[CH:38]=[CH:37][C:31]=2[N:32]=1)#[N:36]
Reactant: CC1=C(C)C(=O)C(C(C)(C)CC(=O)O)=C(C)C1=O
Reactant: N#Cc1nc2ccc(N)cc2s1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(C)(C)CC(=O)Nc2ccc3nc(C#N)sc3c2)=C(C)C1=O
Yield: 10 %

Procedure:
To the solution of 3-methyl-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1-yl)butanoic acid (0.72 g, 3.09 mmol) and isobutyl chloroformate (0.44 g, 3.24 mmol) in 10 ml of dry THF, N-methyl morphorline (0.34 ml) was added at 0° C. The resultant mixture was stirred for 30 minutes at 0° C., and 6-amino-2-cyanobenzothiazole (0.36 g, 2.06 mmol) added. The resultant mixture was stirred overnight. The compound was directly purified with flash silica column using heptane and ethyl acetate as eluent to give a yield 10%. 1H NMR (300 MHz, CD2Cl2) δ 8.57 (d, J=2.0, 2H), 8.06 (d, J=9.0, 2H), 7.67 (s, 1H), 7.40 (dd, J=2.1, 8.9, 1H), 3.08 (s, 2H, CH2), 2.22 (s, 3H, CH3), 2.22 (s, 3H, CH3), 1.99 (s, 3H, CH3), 1.97 (s, 3H, CH3), 1.50 (s, 6H, CH3). MS (m/e): 408 (M+).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[Ca+2].[C:6]1([C:12]2([CH2:17]C3SCCCS3)[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C.O.C(OCC)(=O)C>[C:6]1([C:12]2([CH2:17][CH:1]=[O:4])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc(C2(CC3SCCCS3)CCCC2)cc1
Agent: [Ca+2]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=CCC1(c2ccccc2)CCCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
263 mg (0.969 mmol) of mercuric chloride and 129 mg (1.29 mmol) of calcium carbonate were added to a suspension of 90 mg (0.323 mmol) of 2-(1-phenylcyclopentyl)methyl-1,3-dithiane [prepared as described in step (iv) above] in a mixture of 4 ml of acetonitrile and 0.6 ml of water, and the resulting mixture was stirred for 3 hours at 90° C. At the end of this time, the reaction mixture was cooled and then diluted with ethyl acetate. The insoluble materials were filtered off from the diluted mixture with the help of Celite (trade mark) filter aid. The filtrate was then washed with a 1M aqueous solution of sodium acetate, with a saturated aqueous solution of ammonium chloride and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 5 g of silica gel, using methylene chloride as the eluent, to give 58.4 mg (yield 96%) of the title compound as a foam-like material.
Reaction SMILES: [N:1]1C=CC=[CH:3][CH:2]=1.[C:7]([O:10][C:11](=[O:13])C)(=[O:9])[CH3:8]>C(Cl)Cl>[C:2]([NH2:1])(=[O:9])[CH3:3].[O:10]1[CH2:7][CH2:8][NH:1][C:11]1=[O:13]
Reactant: c1ccncc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(N)=O
Product: O=C1NCCO1
Reaction time: 2 h

Procedure:
To the crude oxazolidinone amine residue 16a in DCM at room temperature was added pyridine (30 equivalents) and acetic anhydride (20 equivalents). The solution was stirred for 2 hrs and concentrated in vacuo. The oxazolidinone acetamide residue was purified by HPLC to provide pure oxazolidinone acetamide.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17](OC)=[O:18])=[C:15]([OH:16])[C:4]1=2)[CH3:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>C1(C)C(C)=CC=CC=1>[CH2:1]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[S:12](=[O:23])(=[O:22])[N:13]([CH3:21])[C:14]([C:17]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[O:18])=[C:15]([OH:16])[C:4]1=2)[CH3:2]
Reactant: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)OC)=C2O
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CCn1c2c(c3ccccc31)S(=O)(=O)N(C)C(C(=O)Nc1ccccn1)=C2O
Yield: 72 %

Procedure:
5-Ethyl-2,5-dihydro-4-hydroxy-2-methyl-N-(2-pyridyl)-1,2 thiazino[5,6-b]indole-3-carboxamide 1,1-dioxide was prepared analogous to Example 15 from methyl 5-ethyl-2,5-dihydro-4-hydroxy-2-methyl-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 72% of theory. M.p.: 232° C. (decomposition, from xylene).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([CH:21]([C:23]3[S:27][C:26]4[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=4[CH:24]=3)[OH:22])[CH2:17][CH2:16]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[S:27]1[C:23]([C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]1=2
Reactant: OC(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(c1cc2ccccc2s1)C1CCN(CCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Dissolve oxalyl chloride (4.22 g, 33.28 mmol) in methylene chloride (200 mL), place under an argon atmosphere and cool to -78° C. Add, by dropwise addition, dimethylsulfoxide (5.4 2 g, 69.33 mmol) and stir at -78° C. for 15 minutes. Add, by dropwise addition, a solution of α-[1-(2-phenylethyl)-4-piperidinyl]-2-benzo[b]thiophenemethanol (9.75 g, 27.73 mmol) in dimethylsulfoxide (150 mL). Stir at -78° C. for 30 minutes, add triethylamine (15.18 g, 0.150 mol) and stir at -78° C. for 1 hour. Remove the ice bath and stir for an additional 1.5 hours. Evaporate the solvent in vacuo and recrystallize (isopropanol) to give the title compound as fluffy white crystalline solid; mp 129°-130° C.
Reaction SMILES: [S:1](=[O:4])(=[O:3])=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](O)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:1]([O:4][S:19]([C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)(=[O:21])=[O:20])(=[O:3])=[O:2])=[CH:8][CH:7]=1
Reactant: Clc1ccccc1
Reactant: O=S(=O)(O)c1ccc(Cl)cc1
Reactant: O=S(=O)=O
Product: O=S(=O)(OS(=O)(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1

Procedure:
p-Chlorobenzenesulfonic anhydride was prepared, as described in the previous example, by reacting 9.4 g (0.12 mole) of sulfur trioxide with 6.0 g (0.054 mole) of chlorobenzene. There was obtained 5.7 g (57.2% yield) of product with mp 140.0°-147.3° C. (lit. 130°-141° C. Christensen, Acta Chem. Scand. 15, 1507 (1961); lit. mp for p-chlorobenzenesulfonic acid =50.5° C., Dictionary of Org. Cpds., Vol. 2, 4th Edition, Oxford Univ. Press, N.Y., p. 601). Anal: Calc'd for C12H8O5S2Cl2 : C, 39.23; H, 2.17; S, 17.34. Found: C, 39.20; H, 2.50; S, 17.61.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([N:15]([C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[C@H:16]([C:18](O)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.Cl.[CH2:36]([O:38][C:39](=[O:46])[C@@H:40]1[CH2:44][CH:43]([OH:45])[CH2:42][NH:41]1)[CH3:37].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH2:36]([O:38][C:39](=[O:46])[C@@H:40]1[CH2:44][CH:43]([OH:45])[CH2:42][N:41]1[C:18](=[O:19])[C@H:16]([CH3:17])[N:15]([C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:21]([O:23][CH2:24][C:25]([Cl:27])([Cl:28])[Cl:26])=[O:22])[CH3:37]
Reactant: CCOC(=O)[C@@H]1CC(O)CN1
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CC(O)CN1C(=O)[C@H](C)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](CCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 40.7 %

Procedure:
To N-[(1S)-1-(ethoxycarbonyl)-3-phenylpropyl]-N-(2,2,2-trichloroethoxycarbonyl)-L-alanine (5.94 g, 13.07 mmol) in 50 ml methylene chloride, under N2, was added oxalyl chloride (5.70 ml, 65.33 mmol) and then N,N-dimethylformamide (20 uL). The solution was stirred 3.5 hours and concentrated in vacuo. The residue was diluted with 30 ml methylene chloride and cooled with an ice bath while under N2. To this solution was added portionwise a mixture of 4-hydroxy-L-proline ethyl ester hydrochloride (1.96 g, 10.05 mmol) and triethylamine (6.99 ml, 50.25 mmol) in 40 ml methylene chloride. After the addition was complete the solution was slowly warmed to room temperature, stirred 18 hours and concentrated in vacuo. The residue was dissolved in ether and washed with water, 10% HCl, 1N NaOH, and brine, and dried (MgSO4) and concentrated in vacuo. Chromatography of the residue on HPLC, using 50% ethyl acetate in hexanes as eluents, provided 2.44 g (41%) of the oily product.
Reaction SMILES: [CH3:1][CH:2]([O:4]C(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[C:34]([OH:38])[CH:35]=[CH:36][CH:37]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCCC1OCCO>C1COCC1>[F:40][C:16]([F:15])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:33]=[C:34]([CH:35]=[CH:36][CH:37]=4)[O:38][CH2:1][CH2:2][OH:4])[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1
Reactant: Oc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Reactant: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: OCCOC1CCCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OCCOc1cccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 53.4 %

Procedure:
DIAD (0.081 mL, 0.41 mmol) was added dropwise to 3-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenol (obtained as described in Example 670, preparation of starting materials) (125 mg, 0.34 mmol), triphenylphosphine (108 mg, 0.41 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (60.4 mg, 0.41 mmol) in THF (3 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 4 hours, then added to an SCX column. The crude product was eluted from the column using 2M ammonia in methanol and the solvents were evaporated. The crude product was purified by flash silica chromatography, elution gradient 80 to 100% EtOAc in isohexane. Fractions containing product were evaporated then further purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(3-(1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl)phenoxy)ethanol (74 mg, 53%) as a solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][N:4]=1.ClC1N=C(CCl)C=CC=1.[C:20]1([P:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[Cl-:1].[CH3:10][O:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][P+:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:8]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccnc(CCl)c1
Agent: ClCc1cccc(Cl)n1
Solvent: Cc1ccccc1
Product: COc1ccnc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Cl-]

Procedure:
The hydroxymethyl compound obtained above was converted to 2-chloromethyl-4-methoxypyridine by the method of Part (iv), above, to provide 0.895 g (5.68 mmole). This was reacted with an equimolar amount of triphenylphosphine in toluene (10 ml) at reflux for 20 hours. The precipitated product was filtered to give 860 mg of the title compound as a yellow solid.
Reaction SMILES: C[O-].[Na+].[CH:4]([NH2:6])=[NH:5].O=[C:8]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10][CH:9]1[C:22](OC)=[O:23].C(O)(=O)C>CO>[OH:23][C:22]1[C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[N:6]=[CH:4][N:5]=1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ncnc(O)c2CC1
Reaction time: 0.25 h

Procedure:
A solution of NaOMe in MeOH (13.6 mL, 25% in MeOH, 59.5 mmol) is added to a stirred solution of formamidine (2.2 g, 21 mmol) in MeOH (50 ml) at rt. The mixture is stirred for 15 min. 1-tert-Butyl 4-methyl 5-oxoazepane-1,4-dicarboxylate (5 g, 7.5 mmol) is added and the mixture is stirred at rt overnight. Acetic acid (2.33 g, 38.5 mmol) is added and the solvent is removed in vacuo. Water (30 ml) is added to the residue and the solution is extracted with DCM (3×30 ml). The combined extracts are washed with brine (40 ml), dried (Na2SO4) and evaporated, to provide a yellow solid that is used in the next step without further purification.
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Solvent: CC#N
Product: O=C(O)C(Nc1ccc(Cl)cc1)c1ccccc1
Temperature: 100 °C
Yield: 47 %

Procedure:
To a solution of α-bromophenylacetic acid (1.00 g, 4.65 mmol) in acetonitrile (20 ml), was added 4-chloro-phenylamine (1.18 g, 9.30 mmol), and the mixture was heated under microwave irradiation at 100° C. for 1 hour (UPLC-MS monitoring: complete conversion). The solvent was evaporated, and the residue was positioned between EtOAc and 1N HCl. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain intermediate I11 (0.57 g; 47% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([C:19]([OH:21])=O)=[C:11]2[O:12][C:13]=1[CH3:14].O=S(Cl)[Cl:24]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([C:19]([Cl:24])=[O:21])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)Cl

Procedure:
A mixture comprising 3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid (Intermediate IBB) (1 g, 3.08 mmol) and SOCl2 (10 ml, 137 mmol) is heated at reflux for 2 hours. After cooling to room temperature excess SOCl2 is removed under vacuum. The resulting solid is azeotroped with toluene until any remaining SOCl2 is removed to afford the title compound as a solid; 1H NMR (400 MHz, CDCl3) δ 2.48 (s, 3H), 2.53 (s, 3H), 7.48 (q, 1H), 7.52 (q, 1H), 7.62 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26]Cl)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.[CH3:37][O:38][CH:39]([Si](C)(C)C)[CH3:40].C[CH2:46][N:47](C(C)C)C(C)C>N1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH2:26][N:47]4[CH2:40][CH2:39][O:38][CH2:37][CH2:46]4)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(C)[Si](C)(C)C
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(F)cc1C1N(CCCCl)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1COCCN1
Product: Cc1ccc(F)cc1C1N(CCCN2CCOCC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 120 °C
Reaction time: 4 h
Yield: 37.3 %

Procedure:
The mixture of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-(3-chloro-propyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.24 g, 0.36 mmol) prepared in example 60a and morpholine (10 mL) was heated at 120° C. for 1 h. The mixture was concentrated to dryness. The resulting residue was added dichloromethane (20 mL) and then trifluoroacetic acid (20 mL). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was separated and concentrated. The residue was redissolved in methanol (10 mL). To the resulting solution was added N,N′-diisopropylethylamine (2 mL, 11.0 mmol) and the crude was heated at 100° C. for 1 h. The reaction mixture was concentrated and the residue was purified by chromatography (MeOH:EtOAc=1:9) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-1′-(3-morpholin-4-yl-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.08 g, 37.9%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Br:13][CH:14](C)C(Br)C.S([O-])(O)(=O)=O.[C:24]([NH3+])([CH3:27])([CH3:26])C>C(Cl)Cl>[Br:13][CH2:14][CH2:26][CH2:24][CH2:27][O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH2:2][CH2:3]2
Reactant: Oc1ccc2c(c1)CCC2
Reactant: CC(C)(C)[NH3+]
Reactant: CC(Br)C(C)Br
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: BrCCCCOc1ccc2c(c1)CCC2
Reaction time: 14 h

Procedure:
5-Indanol (1 g, 7.45 mmol) in NaOH(aq) (5.22 mL, 20.88 mmol, 4 M soln.) was treated with dibromobutane (3.38 mL, 28.3 mmol) and t-butylammoniumhydrogensulfate (catalytic). The solution was placed in a Robbins™ oven for 14 hours at 99° C. Upon cooling, the pH was adjusted to ˜8 with 4 N NaOH. CH2Cl2 was then added and the solution washed with H2O (×2) and brine. The organic layer was dried over MgSO4 and concentrated to an oil. The oil was then dissolved in 4:1 hexane/EtOAc and passed through a plug of silica gel which was then washed with 4:1 hexane/EtOAc. The filtrate was concentrated to afford 4-bromo-1-indan-5-yloxybutane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].OS(O)(=O)=O.[OH-:17].[Na+].[CH3:19][C:20](O)=[O:21]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:21][CH2:20][CH3:19])=[O:17]
Reactant: [OH-]
Reactant: CC(=O)O
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 m/nol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 h to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The PH of the solution was adjusted to 4 with NaOH (aq.). The mixture was extracted with more ethyl acetate. The organic layer was washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 h. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 h and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation with a hydrogen balloon converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.