Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)[CH:10]=[CH:11][C:12]=1[Cl:13].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[N:35]1[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]1)[C:29](O)=[O:30].N1C=CC=CC=1>O>[Cl:13][C:12]1[CH:11]=[CH:10][C:9]([NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[NH:6][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:34]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[C:26]([F:25])[CH:27]=1
Reactant: N#Cc1ccc(C(=O)Nc2ccc(Cl)c(N)c2)cc1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2F)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(c2ccc(C(=O)Nc3cc(NC(=O)c4ccc(C#N)cc4)ccc3Cl)cc2F)CC1
Temperature: -10 °C
Reaction time: 16 h
Yield: 58.5 %

Procedure:
Phosphoryl chloride (0.1 I ml) was added dropwise to a stirred mixture of N-(3-amino-4-chlorophenyl)-4-cyanobenzamide (0.2 g), 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid (0.26 g) and pyridine (2 ml) which had been cooled to −10° C. The reaction mixture was allowed to warm to ambient temperature and was stirred for 16 hours. The mixture was diluted with water and was stirred overnight. The precipitate was isolated, washed with diethyl ether and dried under vacuum at 55° C. There was thus obtained the title compound as a solid (0.212 g);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[CH3:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)=[O:13].[OH-].[Na+].Cl>O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=CC(=O)c2ccc(O)cc2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 80.4 %

Procedure:
Into an ethanol solution (5 liters) comprising 500 g (3.67 moles) of anisaldehyde and 500 g (3.67 moles) of 4-hydroxyacetophenone was dropped an aqueous solution (600 ml) of 250 g of sodium hydroxide in about 80 minutes in a stream of nitrogen. Thereafter, the mixture was heated to 50° C. and agitated for 24 hours. The reaction mixture was cooled down to room temperature, to which were added 2 liters of 12% hydrochloric acid and then 4 liters of water, whereupon crystals settled. The crystals were collected by filtration and quickly washed with ethanol, followed by drying under reduced pressure to obtain 750 g of the intended compound (2.95 moles, yield 80%). The compound was recrystallized from ethanol to obtain light yellow prismatic purified crystals. The melting point and various spectral data of the compound coincided with those of a reference compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:11]>[Pd].C(O)C.O1CCCC1>[ClH:11].[F:1][C:2]1[C:3]([CH2:9][NH2:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1ncc(F)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NCc1ncc(F)cc1F
Reaction time: 5 h
Yield: 100 %

Procedure:
A mixture of 3,5-difluoropicolinonitrile (1.4 g, 10 mmol), conc. HCl (12 ml) and 10% Pd—C (200 mg) in 1:1 ethanol/tetrahydrofuran was shaken under a hydrogen atmosphere (50 psi) for 5 h. The reaction mixture was filtered and the ethanol removed in vacuo. The remaining solution was lyophilized to afford an off-white solid (2.16 g, 100% yield). LCMS (M+H) calcd for C6H7F2N2: 145.06; found: 145.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[O:22]C)C(O)=O>>[Cl:12][C:13]1[CH:14]=[C:15]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)[CH:19]=[CH:20][C:21]=1[OH:22]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(C(=O)O)cc1Cl
Product: Oc1ccc2oc(-c3ccc(O)c(Cl)c3)nc2c1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 3-chloro-4-methoxybenzoic acid and was obtained as a white solid, m.p. 254–256° C.; MS m/e 260 (M−H)+.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:8]2[C:16](=[O:17])[C:15]3[CH:14]4[C:18]([CH3:20])([CH3:19])[C:11]([CH3:21])([CH2:12][CH2:13]4)[C:10]=3[N:9]2[CH3:22])[CH:5]=[CH:6][CH:7]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.ClCCl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][N:9]1[C:10]2[C@@:11]3([CH3:21])[C:18]([CH3:20])([CH3:19])[C@H:14]([CH2:13][CH2:12]3)[C:15]=2[C:16](=[O:17])[N:8]1[C:4]1[CH:3]=[C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1c2c(c(=O)n1-c1cccc(I)c1)C1CCC2(C)C1(C)C
Reactant: Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ccccc1-c1cccc(-n2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)c1
Yield: 43 %

Procedure:
A mixture of 2-(3-iodo-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Example 23; 80 mg, 0.2 mmol), 2-methyl-phenyl-boronic acid (40 mg, 0.29 mmol), potassium carbonate (66 mg, 0.47 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 0.014 mmol) in dimethoxyethane (4 mL) was sealed under argon and heated at 80 degrees overnight and then at 90 degrees over the weekend. The reaction mixture was diluted with dichloromethane, filtered through a cotton plug and frit, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-35% ethyl acetate/hexanes to give (4S,7R)-1,7,8,8-tetramethyl-2-(2′-methyl-biphenyl-3-yl)-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (32 mg, 44%) as a light brown solid. ES(+)-MS (M+H) 373.
Reaction SMILES: Br[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:25]1[CH2:30][CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1.C(O)(O)=O.COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO.O>[O:25]1[CH2:26][CH:27]=[C:28]([C:2]2[C:3]([O:8][C:9]3[CH:14]=[CH:13][C:12]([NH:15][C:16]4[O:17][C:18]5[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=5[N:20]=4)=[CH:11][CH:10]=3)=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:29][CH2:30]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Brc1cccnc1Oc1ccc(Nc2nc3ccccc3o2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)O
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C1=C(c2cccnc2Oc2ccc(Nc3nc4ccccc4o3)cc2)CCOC1
Temperature: 140 °C

Procedure:
A glass microwave reaction vessel was charged with N-(4-(3-bromopyridin-2-yloxy)phenyl)benzo[d]oxazol-2-amine (0.500 g, 1.308 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.414 g, 1.971 mmol), sodium carbonate anhydrous (0.700 g, 6.60 mmol) and trans-dichlorobis(triphenyl-phosphine)palladium (II) (0.092 g, 0.131 mmol, Strem). A mixture of 7:3:2 DME:H2O:EtOH (11 mL) was added and the reaction mixture was sealed under argon and heated in a Emrys Optmizer microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 140° C. for 15 min. The reaction mixture was partitioned between EtOAc/water and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→1:2) to give a light-orange amorphous solid. MS (ESI, pos. ion) m/z: 386.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:19](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1cccc(-c2n[nH]c3ncccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncccc23)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3-(6-bromo-2-pyridyl)-1H-pyrazolo[5,4-b]pyridine (3.00 g, 10.90 mmol) in dry DMF (30.00 mL) was cooled in an ice-bath. Sodium hydride (479.6 mg, 11.99 mmol) was added in one portion and the resulting mixture changed to a yellow solution and was stirred at 0° C. for 30 minutes. Trityl chloride (3.189 g, 11.44 mmol) was added in one portion and the resulting yellow suspension was stirred at RT for 60 minutes, by which time it was a bright yellow suspension. Analysis by LCMS showed presence of desired product.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12]P(=O)(OCC)OCC)=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].O>C1COCC1.O1CCOCCOCCOCCOCC1>[CH3:1][C:2]1[C:3]([O:8][C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH:12]=[C:36]2[CH2:37][CH2:38][N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:34][CH2:35]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCOP(=O)(Cc1cccc(Oc2ncccc2C)c1)OCC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1Oc1cccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
Diethyl 3-(3-methylpyridin-2-yloxy)benzylphosphonate (4.3 g, 13 mmol) from Step 3 and 1,4,7,10,13-pentaoxacyclopentadecane (15-Crown-5, 0.05 mL, 0.28 mmol) were combined in THF (150 mL). Sodium hydride (564 mg, 60% dispersion in mineral oil, 14.1 mmol) was added. The reaction was stirred for 30 min and then a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1.81 g, 14.1 mmol) in THF (15 mL) was added. After 16 h, water was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10-30%, EtOAc:heptane) to afford the title compound (3.9 g, 80% yield) as a thick oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCOCC2)n1
Yield: 83 %

Procedure:
6-Methylpicolinic acid (1.37 g) and morpholine (870 mg) was dissolved in 30 mL of DMF, and thereto 1.6 g of HOBt was added under stirring at ice temperature. After the mixture was stirred at same temperature for 15 minutes, additionally 2.3 g of WSC was added, and the solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The resulting residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=900:30:1) to give 1.71 g of (6-methylpyridin-2-yl)morpholin-4-ylmethanone as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)=[O:6].[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)=[O:6])[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CCCCl)c1c[nH]c2ccccc12
Reactant: O=C(NC1CCNCC1)c1ccccc1
Product: O=C(NC1CCN(CCCC(=O)c2c[nH]c3ccccc23)CC1)c1ccccc1
Temperature: 160 °C
Yield: 39.8 %

Procedure:
A mixture of 3-(4-chlorobutyryl)indole (22.2g. 0.1 mol.) and 4-benzamidopiperidine (40.8g. 0.2 mol.) was stirred and heated at 160° C. for 1 hour. The melt was cooled and extracted under reflux with water (200 ml.) for 0.5 hour. The insoluble granular residue was collected by filtration and crystallised from a mixture of ethanol (150 ml) and water (50 ml.), with charcoal treatment, to yield the title compound (15.5 g. 40%). The hydrochloride was precipitated from a solution of the base, in ethanol by addition of ethanolic hydrogen chloride (16.2 g. 38%) m.p. 275°-6° C. C24H27N3O. HCl 1/4 H2O requires C, 67.0 H, 6.7; N, 9.8 Found: C, 67.0; H, 6.7; N, 9.7%. It can also be precipitated from a solution of the base in dimethylformamide by addition of ethanolic hydrogen chloride and propan-2-ol. This gives the anhydrous form of the title compound hydrochloride m.p. 285.5° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[CH3:20][C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:26])[CH2:22][C:23](O)=[O:24]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:23](=[O:24])[CH2:22][C:21]([CH3:20])([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[N:11]=2)=[CH:13][CH:14]=1
Reactant: Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O
Reactant: CC(C)(CC(=O)O)c1ccccc1
Product: CC(C)(CC(=O)Nn1nc(-c2ccc(Br)cc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The products from Example 2A and 3-methyl-3-phenylbutanoic acid were treated using a method similar to that described in Example 51 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.38 (s, 1H), 8.39-8.42 (m, 1H), 7.88-8.04 (m, 2H), 7.76-7.81 (m, 2H), 7.70-7.77 (m, 1H), 7.53-7.58 (m, 2H), 7.42-7.46 (m, 2H), 7.25-7.36 (m, 2H), 7.15-7.21 (m, 1H), 2.62 (s, 2H), 1.47 (s, 6H); MS (ESI−) M/Z 474 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[F:12][C:13]1[CH:14]=[C:15]([NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:16]=[CH:17][C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Product: COC(=S)c1cc(Nc2ccc(-c3ccccc3)c(F)c2)c(C)s1
Yield: 39.3 %

Procedure:
Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 155.5 mg (2 equiv, 0.72 mmol) of 3-fluoro-4-phenylphenyl boronic acid to give 50.6 mg (41.6%) of methyl 4-[(3-fluoro-4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ2.44 (s, 3H), 3.91 (s, 3H), 6.19 (s, 1H), 6.78-6.86 (m, 2H), 7.32-7.39 (m, 2H), 7.73-7.47 (m, 2H), 7.55 (d, 1H, J=6.9 Hz), 7.82 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH3:19][O:20][C:21]1[CH:32]=[CH:31][CH:30]=[CH:29][C:22]=1[CH:23]=[N+:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:23]([C:22]1[CH:29]=[CH:30][CH:31]=[CH:32][C:21]=1[O:20][CH3:19])[N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1c[nH]c2ccc(OCc3ccccc3)cc12)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole and 1-(2-methoxy-benzylidene)-pyrrolidinium chloride, which had been prepared in accordance with example 24.
Reaction SMILES: N1C[CH2:4][CH2:3][CH2:2]1.CC(C)=O.[C:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[OH:22])[C:16]([OH:18])=[O:17])(=[O:12])[CH3:11]>C(#N)C>[C:16]([C:15]1[CH:14]=[C:13]2[C:21](=[CH:20][CH:19]=1)[O:22][C:3]([CH3:4])([CH3:2])[CH2:11][C:10]2=[O:12])([OH:18])=[O:17]
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2cc(C(=O)O)ccc2O1
Reaction time: 48 h

Procedure:
13.8 g of pyrrolidine and 40 ml of acetone are added to a suspension of 14.7 g (0.0815 mol) of 3-acetyl-4-hydroxybenzoic acid in 200 ml of acetonitrile. The slowly discoloring solution is allowed to stand at room temperature for 2 days, the solvent is distilled off on a rotary evaporator, the residue is treated with water and adjusted to acidic pH<1 using conc. hydrochloric acid and the crystalline substance is filtered off.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][OH:34])=[CH:31][CH:30]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:34][CH2:33][C:32]2[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=2)[CH:7]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3ccc(C(F)(F)F)cc3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 4-(trifluoromethyl)benzyl alcohol (132 mg; 0.736 mmol), example 73 was prepared analogously to the procedure for the preparation of example 42.
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)[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:46]2)=CC=1>C1(C)C=CC=CC=1>[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](=[S:46])[NH:12][CH:11]3[C:24]3[C:29]([O:30][CH:31]([CH3:33])[CH3:32])=[CH:28][CH:27]=[C:26]([F:34])[C:25]=3[F:35])[C:5]2=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Oc1ccc(F)c(F)c1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(F)c(F)c1C1NC(=S)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 77.4 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.45 g, 0.85 mmol) prepared in example 62d was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.6 g, 1.8 mmol) in toluene to give racemic (2′S,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,3-difluoro-6-isopropoxy-phenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.36 g, 78.3%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[C:12]([F:13])[CH:11]=2)[CH:7]=[CH:8]1)[CH3:20]
Reactant: Fc1cc2[nH]ccc2cc1Br
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2cc(Br)c(F)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
NaH (81 mg, 3.21 mmol) was added to a 0° C. solution of 5-bromo-6-fluoro-1H-indole (0.343 g, 1.60 mmol) in THF (16 mL). The reaction mixture was stirred at 0° C. for 15 min, then ethyl bromoacetate (0.535 mL, 4.81 mmol) was added. The reaction was stirred at rt for 1 h, then partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl.N1C=CC=CC=1>[Cl:14][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: ClC1CCCc2ccccc21
Reaction time: 2 h

Procedure:
One hundred grams of 1,2,3,4-tetrahydro-1-naphthol were dissolved in 1 liter of chloroform and 53.9 ml of pyridine. The mixture was cooled with an external ice bath and 98.6 ml of thionyl chloride were added over a 1 hour period. The reaction mixture was stirred an additional 2 hours with cooling, concentrated in vacuo, and the residue taken up in 1 liter of methylene chloride. The methylene chloride solution was washed with water, a 5% sodium bicarbonate solution, water again, dried over sodium sulfate, and evaporated to dryness to provide the desired intermediate 1,2,3,4-tetrahydro-1-chloronaphthalene.
Reaction SMILES: C(OC([CH:6]1[CH2:11][C:10]([C:17]#[N:18])([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)[CH2:9][CH2:8][C:7]1=[O:19])=O)C.O.[OH-].[Na+]>Cl.C(O)(=O)C>[O:19]=[C:7]1[CH2:8][CH2:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)([C:17]#[N:18])[CH2:11][CH2:6]1
Reactant: CCOC(=O)C1CC(C#N)(c2ccsc2)CCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1(c2ccsc2)CCC(=O)CC1
Reaction time: 4 h
Yield: 43.5 %

Procedure:
5-cyano-2-oxo-5-thiophen-3-yl-cyclohexanecarboxylic acid ethylester (40 g; 0.14 mole) dissolved in a mixture of concentrated hydrochloric acid (200 ml) and glacial acetic acid (400 ml) was heated with stirring for about 4 hours to reflux. On completion of the reaction (reaction monitored by thin layer chromatography), water (100 ml) was added and neutralized with aqueous sodium hydroxide solution (200 ml) and extracted with ethylacetate (2×400 ml). The organic phase was washed with sodium hydrogen carbonate solution (200 ml) and water (100 ml), dried (sodium sulfate) and concentrated under vacuum. Purification by column chromatography (silica gel, 25% ethylacetate in n-hexane) yielded 12.5 g 4-oxo-1-thiophen-3-yl-cyclohexanecarbonitrile (42%; pale yellow solid).
Reaction SMILES: [SH:1][CH2:2][C:3]1([OH:15])[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:16]1(=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]1=[O:26]>>[C:9]1([CH:6]2[CH2:5][CH2:4][C:3]3([O:15][C:19]4[C:20]5[C:25]([C:16](=[O:27])[C:17](=[O:26])[C:18]=4[S:1][CH2:2]3)=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:8][CH2:7]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=Cc2ccccc2C1=O
Reactant: OC1(CS)CCC(c2ccccc2)CC1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCC(c3ccccc3)CC1)O2

Procedure:
The crude 1-(mercaptomethyl)-4-phenylcyclohexanol was then reacted with naphthalene-1,2-dione as outlined in procedure F [both step (i) and (ii)] to afford crude 4-phenylspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione. The crude 4-phenylspiro[cyclohexane-1,2′-naphtho[1,2-b][1,4]oxathiine]-5′,6′-dione was purified by flash column chromatography (SiO2, 100% dichloromethane) to afford the product as a purple solid. M.p.=183-187° C.; 400 MHz 1H NMR (DMSO) δ: 7.92-7.78 (m, 3H), 7.60-7.56 (td, 1H), 7.34-7.18 (m, 5H), 3.09 (s, 2H), 2.71-2.66 (m, 1H), 2.20 (d, 2H), 1.90-1.72 (m, 6H); LCMS: 377 [M+H].