Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])([O-])=O.[Ca+2].[N+]([O-])([O-])=O.[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1>ClCCl>[CH2:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17].[CH2:17]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[CH3:10]
Reactant: Cc1ccc(C)cc1
Reactant: Cc1ccccc1
Agent: O=[N+]([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Product: CCc1ccc(C)cc1
Product: CCc1ccccc1
Yield: 86 %
Yield: 89 %

Procedure:
Pilot-scale treatments also support the laboratory incubations. The addition of calcium nitrate to the sediments of the Dofasco Boatslip in 1992 resulted in the biodegradation of several organic compounds (mean of three samples, reductions as follows; toluene 80%, ethylbenzene 86%, m/p-xylene 76%, 3/4-ethyltoluene 89%, and dichloromethane 65%) (FIG. 29). These relatively rapid biodegradation rates are similar to those reported in laboratory studies where nitrate was added to enhance biodegradation (Hutchins 1991).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:15]=2)[O:10][C:9]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].[Na]>ClCCl>[C:1]([O:5]/[N:6]=[C:7]1\[CH:8]=[C:9]([C:22]2[N:23]=[CH:24][C:25]3[C:30]([CH:31]=2)=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:10][C:11]2[C:16]\1=[CH:15][CH:14]=[C:13]([C:17]#[C:18][CH2:19][CH2:20][O:21][S:40]([CH3:39])(=[O:42])=[O:41])[CH:12]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#CCCO)ccc12
Reactant: CS(=O)(=O)Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)O/N=c1\cc(-c2cc3ccccc3cn2)oc2cc(C#CCCOS(C)(=O)=O)ccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cold solution of 7-(4-Hydroxy-but-1-ynyl)-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (tert-butyl protected oxime of example 52) (200 mg, 0.485 mmol) and triethylamine (0.15 ml, 1.067 mmol) in dichloromethane (3 ml) was added dropwise methanesulfonyl chloride (75 μl, 0.970 mmol). The reaction mixture was stirred for 1.5 hours at 0° C. and poured onto a saturated solution of sodium hydrogenocarbonate. The product was extracted with dichloromethane, washed with brine, dried over sodium sulfate and concentrated to dryness to yield methanesulfonic acid 4-{4-[(E)-tert-butoxyimino]-2-isoquinolin-3-yl-4H-chromen-7-yl}-but-3-ynyl ester. The methansulfonic ester was dissolved in dimethylformamide (4 ml) and treated with potassium carbonate (201 mg, 1.46 mmol) and methyl piperazine (73 mg, 0.728 mmol) and the mixture was stirred at 40° C. for 20 hours. The mixture was poured onto a saturated solution of sodium hydrogenocarbonate. The reaction mixture was extracted with dichloromethane, washed with water, brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-45%) to yield 7-(but-3-en-1-ynyl)-2-Isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (156 mg, 82%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[C:19]1([CH2:25]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C>[CH2:25]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([N:8]1[CH:7]=[C:6]2[C:10]([CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5]2)=[N:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2ccccc2)c1
Product: O=[N+]([O-])c1ccc2nn(Cc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 10 g (61.3 mmol) of 5-nitroindazole in DMF (100 mL) was added K2CO3 (12.7 g, 91.9 mmol) and PhCH2Br (7.29 mL, 61.3 mmol). The resulting mixture was stirred at RT for 3.5 days, then poured into 400 mL of water. The resulting slurry was filtered, rinsed once with water and dried in vacuo giving a beige solid. A 2.5 g portion of this crude material was purified by chromatography (SiO2, elution with 1:2 EtOAc-hexanes) giving 1-benzyl-5-nitro-1H-indazole and 2-benzyl-5-nitro-2H-indazole.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][C:11]([CH:17]=O)=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[CH2:28][C:29](=[O:35])[NH:30]3)[CH:23]=[CH:24][CH:25]=1>N1CCCCC1.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2/[C:28](=[CH:17]/[C:11]2[NH:12][C:13]4[CH2:14][CH2:15][CH2:16][CH:8]([CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:9]=4[CH:10]=2)/[C:29](=[O:35])[NH:30]3)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2)N1
Reactant: O=Cc1cc2c([nH]1)CCCC2CCN1CCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2cccc(-c3cccc(F)c3)c2/C1=C/c1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
4-(2-Pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (0.2 was condensed with 4-(3-fluoro-phenyl)-1,3-dihydro-indol-2-one (0.2 mmol) and piperidine (2 drops) in ethanol at rt for overnight. The solvent was removed and the residue was purified on a silica gel column to give 25 mg of the titled compound as a yellow solid.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:2]1.[Li:16]CCCC>CCCCCC>[N:10]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:1]([Li:16])[CH:2]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: C1=C(N2CCCCC2)c2ccccc2C1
Reactant: [Li]CCCC
Solvent: CCCCCC
Product: [Li]C1C=C(N2CCCCC2)c2ccccc21
Reaction time: 24 h
Yield: 95 %

Procedure:
1-(1H-inden-3-yl)piperidine (3.00 g, 15.1 mmol) was dissolved in 75 mL of hexane and 7.1 mL of 2.5 M n-BuLi (1.09 eq) was added dropwise via syringe over a 5 minute period. The solution developed a yellow precipitate upon the addition of the first 0.5 mL of n-BuLi. The resulting slurry was allowed to stir 24 hours. After this time the solid was filtered, washed with 50 mL of hexane and allowed to dry in vacuo overnight to afford the desired anion as a yellow solid (2.96 g, 14.3 mmol) in 95 percent yield.
Reaction SMILES: [NH2:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[CH2:6][CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH:21]1([C:24]([Cl:26])=O)[CH2:23][CH2:22]1>>[ClH:26].[CH:21]1([C:24]2[O:20][C:19]3[C:2]([N:1]=2)=[CH:3][C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=2[CH:18]=3)[CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)c(O)cc2CC1
Product: Cl
Product: c1c2c(cc3oc(C4CC4)nc13)CCNCC2
Yield: 81 %

Procedure:
The title compound was prepared in analogy to General Procedure 2 from 1,1-dimethylethyl 7-amino-8-hydroxy-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 9, 2.16 mmol) and cyclopropanecarbonyl chloride (2.4 mmol) to give the title compound (1.75 mmol) as a white solid.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[CH:6]([CH:8]=[O:9])=[O:7]>C(O)CCCCCCC>[C:8]([O:5][CH2:1][CH2:2][CH2:3][CH2:4][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[CH:6]=[O:7].[C:8]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])(=[O:9])[CH:6]=[O:7]
Reactant: CCCCO
Reactant: O=CC=O
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(=O)C=O
Product: CCCCOC(=O)C=O

Procedure:
5.17 g of the butanol solution of glyoxal obtained in Example 2-11, 9.62 g of 1-octanol, and 0.6 g of the above-mentioned metal-loading carrier were put into an autoclave, and an oxidation reaction was conducted by the same operation as in Example 2-11. The reaction solution thus obtained was analyzed, which revealed the glyoxal conversion to be 90%, and the combined 1-octyl glyoxylate and 1-butyl glyoxylate (the product) selectivity and yield to be 74% and 67%, respectively.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:29][CH2:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25]3)[C:8]2([NH:15][C@@H](C2C=CC=CC=2)CO)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1>C(Cl)Cl.CO>[NH2:15][C:8]1([C:11]([O:13][CH3:14])=[O:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:10]=2)[CH2:6][C:7]21[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[CH2:28][CH2:29]2
Reactant: COC(=O)C1(N[C@H](CO)c2ccccc2)c2cc(Br)ccc2CC12CCC(OC)CC2
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1(N)c2cc(Br)ccc2CC12CCC(OC)CC2
Reaction time: 2 h
Yield: 123.1 %

Procedure:
To a solution of methyl 6′-bromo-1′-(((S)-2-hydroxy-1-phenylethyl)amino)-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate (0.0180 g, 0.03 mmol) in CH2Cl2 (3 mL) and MeOH (1.5 mL) was added Pb(OAc)4 (0.0500 g, 0.11 mmol) at 0° C. The mixture was stirred for 2 h. After the solvents were evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0136 g (94%) of methyl 1′-amino-6′-bromo-4-methoxy-1′,3′-dihydrospiro[cyclohexane-1,2′-indene]-1′-carboxylate as a TFA salt. LC-MS tR=1.11 min in 3 min chromatography, m/z 368, 370 (MH), 351, 353, 319, 321; 1H NMR (400 MHz, CD3OD) δ 7.57-7.54 (m, 2H), 7.31 (d, J=8 Hz, 1H), 3.79 (s, 3H), 3.35 (s, 3H), 3.25-3.15 (m, 2H), 3.04 (d, J=16 Hz, 1H), 2.09-2.06 (m, 2H), 1.61-1.29 (m, 6H); 13C NMR (100 MHz, CD3OD) δ 170.36, 143.46, 140.64, 134.50, 128.89, 128.09, 121.70, 79.44, 75.22, 56.11, 54.06, 52.58, 39.97, 31.11, 29.52, 29.44, 28.88.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:14]2[CH2:17][CH2:16][CH2:15]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].P(OCC)(OCC)([S-])=[S:19]>O>[C:1]([C:3]1[C:4]([CH:14]2[CH2:15][CH2:16][CH2:17]2)=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])(=[S:19])[NH2:2]
Reactant: COC(=O)c1cc(C#N)c(C2CCC2)cc1C
Reactant: CCOP(=S)([S-])OCC
Solvent: O
Product: COC(=O)c1cc(C(N)=S)c(C2CCC2)cc1C
Temperature: 80 °C
Yield: 78 %

Procedure:
To a round-bottom flask was added methyl 5-cyano-4-cyclobutyl-2-methylbenzoate (compound 6.4, 3.63 g, 0.015 mol), O,O′-diethyl dithiophosphate (10 mL) and water (1 mL). The reaction mixture was heated to 80° C. for 3 hours (CAUTION: significant gas evolution occurs—this and all other reactions described herein should be carried out in well ventilated fume hoods). After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed successively with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (hexanes/ethyl acetate=80/20 to 50/50) to yield the title compound as a yellow solid (3.06 g, 78% yield). m/z (ES+) 264 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 7.93 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 6.92 (s, 1H), 4.19 (m, 1H), 3.89 (s, 3H), 2.64 (s, 3H), 2.40 (m, 2H), 2.29-2.15 (m, 2H), 2.12-2.00 (m, 1H), 1.95-1.84 (m, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].FC(F)(F)C(O)=O.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH:30]=O)[C@H:26]([CH2:28][CH3:29])[CH3:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.CN(C=O)C>[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH:26]([CH3:27])[CH2:28][CH3:29])[CH2:30][NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:23])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Reactant: CC[C@H](C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCC(C)[C@@H](CN[C@H](C(=O)O)[C@@H](C)CC)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 84 %

Procedure:
Isoleucine (1.31 g, 9.95 mmol) was suspended in anhydrous methanol (10 ml) and trifluoroacetic acid (1.133 g, 0.77 ml, 9.95 mmol) was added. The mixture was stirred until all the isoleucine had dissolved and the solvent was then removed under reduced pressure. Anhydrous DMF (10 ml) was added to the resulting isoleucine trifluoroacetate salt followed by 3 Å molecular sieves and a solution of 2 (1.47 g, 4.9 mmol) in anhydrous DMF (5 ml). After 15 minutes the solution was treated with sodium triacetoxy borohydride (1.58 g, 7.45 mmol) and stirred overnight. The resulting suspension was filtered through celite, diluted with ethyl acetate (50 ml) and washed with saturated sodium chloride solution (2×35 ml). The organic extracts were dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure to yield the acid (1.36 g, 84%) as a yellow oil.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:34][CH2:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:40](=[O:41])[C:39]3[CH:43]=[CH:44][C:36]([CH2:35][Cl:34])=[CH:37][CH:38]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH:9]1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(CCN1CC[C@H](Cc2ccccc2)[C@H](O)C1)c1ccc(O)cc1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CCC(Cc3ccccc3)C(O)C2)cc1)c1ccc(CCl)cc1
Yield: 39.8 %

Procedure:
To a solution of 500 mg (1.33 mmol) (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenol in 10 ml CH2Cl2 were added 20 mg (0.16 mmol) DMAP and 162 mg (1.60 mmol) Et3N and 302 mg (1.60 mmol) 4-chlormethylbenzoylchloride. After 1 hour water was added and the aequous phase was extracted with methylenechloride (3×20 ml). The combined organic layers were dried over MgSO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by chromatography over silica gel to give 280 mg (0.53 mmol, 40%) 4-chloromethyl-benzoic acid 4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as colorless foam.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.B.C1COCC1.[Li]CCCC.CC(S([N:23]=[C:24]1[CH2:27][O:26][CH2:25]1)=O)(C)C.Cl.O1CCOCC1.[Cl:35][C:36]1[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)=[CH:38][C:39]([C:42](O)=[O:43])=[N:40][CH:41]=1>C1COCC1.CO>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:24]1([NH:23][C:42]([C:39]2[CH:38]=[C:37]([O:45][CH2:46][CH:47]3[CH2:48][CH2:49]3)[C:36]([Cl:35])=[CH:41][N:40]=2)=[O:43])[CH2:25][O:26][CH2:27]1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: c1cocn1
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Agent: B
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1(c2ncco2)COC1)c1cc(OCC2CC2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxazole (217 mg, 3.14 mmol) in 8 mL dry THF under argon at room temperature was added BH3.THF (3.14 ml, 3.14 mmol), the reaction mixture was stirred at room temperature for 15 minutes, cooled down to −75° C. followed by slow addition of BuLi (1.96 ml, 3.14 mmol). The resulting reaction mixture was stirred at −75° C. for 30 minutes and a solution of 2-methyl-N-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7, 0.5 g, 2.85 mmol) in 4 mL dry THF was added. The reaction mixture was stirred at −75° C. for 30 minutes, then the reaction was let to warm up to room temperature and was stirred for 1 hour. The reaction was quenched by addition of 1 mL of an aqueous solution 7N ammonium chloride and reaction mixture was stirred for 15 minutes. The mixture was diluted with ethylacetate, poured into a separatory funnel and extracted with water. The organic phase was collected, dried over sodium sulfate and evaporated down to dryness to give a yellow oil. The crude material was used without any further purification. To a solution of the former crude oil (697 mg, 2.85 mmol) in methanol (9 ml) cooled down to 0° C. was added a 4.0M solution of hydrochloric acid in dioxane (2.14 ml, 8.56 mmol). The reaction mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated in vacuo, the residue was dissolved in diethyl ether and a precipitate formed. The suspension was stored in the fridge for 2 hours and then precipitate was collected by filtration. The collected solid was dried under high vacuum for 2 hours to give a crude yellow solid which was used without any purification. The crude solid was used to synthesize the title compound in analogy to Example 24d, using 5-Chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 4a) as starting material and could be isolated (15 mg, 39%) as white solid; MS (ESI, m/z): 350.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: Fc1cc(F)cc(CCl)c1
Product: COc1ccccc1C1CCN(C(=O)c2cn(Cc3cc(F)cc(F)c3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 1-chloromethyl-3,5-difluoro-benzene gave the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([OH:22])[CH2:20][OH:21].[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:21][CH2:20][CH2:19][OH:22])[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCOc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine ((the product of example 1 step ii), 5 g) and ethylene glycol (1.517 g) in THF (100 ml) was added NaH (1.3 g) slowly and the reaction was then allowed to stir overnight at RT. The reaction mixture was then partitioned between EtOAc (200 ml) and H2O (200 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×200 ml). Organics were combined, dried (MgSO4) and reduced in vacuo and the resulting residue was purified by column chromatography on silica gel 10% EtOAc/90% iso-Hex to give the subtitle compound as a clear oil. Yield: 2.4 g
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][C:35]([CH3:37])=O.Cl>CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH:35]([CH3:37])[CH3:34])[CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: CC(C)=O
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CCOCC
Product: CC(C)N1CCC(c2cccc(S(=O)(=O)N3CCN(c4ccc(F)cc4C(F)(F)F)C[C@H]3C)c2)CC1

Procedure:
Prepared according to the synthesis of Example 29EZ in Step 4D from (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-ylphenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) and acetone (23 μL, 0.31 mmol) as a sticky oil (75 mg, 92%). It was redissolved in Et2O and acidified with 1N HCl in Et2O and triturated with hexanes/Et2O to give the titled compound as a white solid. HRMS: calcd for C26H33F4N3O2S+H+, 528.23023. found (ESI-FTMS, [M+H]1+), 528.22834.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[C:10]2[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]1=2.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[C:27]3[CH:26]=[N:25][C:24]([CH3:23])=[CH:29][CH:28]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc2c(c1)c1c(n2-c2ccccc2Br)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccccc2-c2ccc(C)nc2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 0.564 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (247 mg, 1.12 mmol) and K2CO3 (233.48 mg, 0.845 mmol) in DME-water (2:1) was added Pd(PPh3)4 (32.58 mg, 0.028 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue obtained was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(6-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 8.18 (s, 1H), 7.74 (m, 4H), 7.38-7.58 (m, 2H), 7.28 (s, 1H), 6.93 (d, 1H), 6.78 (d, 1H), 4.4 (m, 2H), 3.7 (m, 2H), 3.1 (s, 3H), 2.8 (m, 2H), 2.57 (s, 3H), 2.38 (s, 3H).