Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:11]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A mixture of 2′-hydroxyacetophenone (68.1 g, 0.500 mol), benzylbromide (94.1 g, 0.550 mol) and K2CO3 (103 g, 0.750 mol) in acetone (1.0 L) was heated at reflux, and the stirring was continued overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with water, and extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by distillation under reduced pressure to give 1-[2-(benzyloxy)phenyl]ethanone as a colorless oil. (100 g, yield; 88%)
Reaction SMILES: C1(S[CH2:8][N:9]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[C:17]=3[CH2:21][CH2:22][CH3:23])[S:10]2(=[O:12])=[O:11])C=CC=CC=1.S(Cl)([Cl:31])(=O)=O>>[Cl:31][CH2:8][N:9]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([O:26][CH3:27])=[C:16]([O:24][CH3:25])[C:17]=2[CH2:21][CH2:22][CH3:23])[S:10]1(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCc1c(OC)c(OC)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Product: CCCc1c(OC)c(OC)cc2c1C(=O)N(CCl)S2(=O)=O
Yield: 97 %

Procedure:
By the method of Example 22A 3,4-dimethoxy-2-propyl-N,N-dimethylbenzamide (9.2 g) was aminosulfonylated with sulfur dioxide and hydroxylamine-O-sulfonic acid (5.6 g) to give 2-aminosulfonyl-4,5-dimethoxy-6-propyl-N,N-dimethylbenzamide (7.4 g, 63% yield), which was cyclized in quantititive yield to 4-propyl-5,6-dimethoxysaccharin, phenylthiomethylation of which with chloromethyl phenyl sulfide (1.42 mL) gave 2-phenylthiomethyl-4-propyl-5,6-dimethoxy-saccharin (4.07 g), reaction of part (3.59 g) of which with sulfuryl chloride (2.12 mL) gave 2-chloromethyl-4-propyl-5,6-dimethoxysaccharin, 2.84 g, 97% yield.
Reaction SMILES: CC[O:3][C:4]([CH:6]1[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5].[OH-].[Li+]>C1COCC1.CO.O>[C:18]([O:17][C:15]([N:14]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7][CH:6]1[C:4]([OH:5])=[O:3])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C1Cc2cccnc2N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.2 %

Procedure:
A suspension of 2,3-dihydro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (1 g) and lithium hydroxide (0.25 g) in 6 ml THF, 3 ml MeOH and 3 ml water was stirred 0.5 h at rt. The reaction mixture was poured onto 1M HCl/ice and washed three times with dichloromethane. The aqueous layer was neutralized with 1M NaOH, evaporated to dryness and purified by chromatography (silica gel, dichloromethane/methanol, 4/1) to yield 2,3-dihydro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester as a white solid (400 mg). MS: 263.4 (M−H)−
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:22]
Reactant: O=S(Cl)Cl
Reactant: OCCCCCCCCCCCBr
Solvent: c1ccncc1
Solvent: O
Product: ClCCCCCCCCCCCBr
Temperature: 25 °C

Procedure:
In a 250 mL three-necked flask, 11-bromoundecanol (10 g, 39.8 mmol), pyridine (2 mL, 24.7 mmol) and thionyl chloride (10 mL, 137 mmol) were successively introduced. The solution was stirred at room temperature and the reaction was followed by IR. After disappearance of the OH band, the mixture was hydrolysed carefully by addition of water, the aqueous layer was extracted three times with diethyl oxide. The organic layers were washed successively with a 10% HCl aqueous solution, water, a saturated aqueous solution of NaHCO3 and water until neutrality. After drying over MgSO4 and elimination of solvents under reduced pressure, the oil was filtered on silica gel (eluent:pentane). A colourless oil was obtained (10.15 g, 35 mmol).
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[S:6])[CH2:2][CH3:3].C(N(CC)CC)C.Br.[NH2:15][C:16]1[C:21]([C:22]([OH:24])=O)=[CH:20][C:19]([Br:25])=[CH:18][N:17]=1.C(O)C>CN(C)C=O>[Br:25][C:19]1[CH:18]=[N:17][C:16]2[NH:15][C:5](=[S:6])[N:4]([CH2:1][CH2:2][CH3:3])[C:22](=[O:24])[C:21]=2[CH:20]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: CCCN=C=S
Agent: Br
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCn1c(=S)[nH]c2ncc(Br)cc2c1=O
Temperature: 25 °C

Procedure:
A mixture of n-propyl isothiocyanate (1.59 g, 1.62 mL), triethylamine (5.0 g, 13.8 mL), and 5.0 g of the title compound of Step A was heated to 100-110° C. in 22 mL of dimethylformamide for 48 h. The reaction mixture was then allowed to cool to room temperature and treated with 10 mL of ethanol. The resulting precipitate was filtered, washed with ethanol followed by hexanes and dried to deliver 2.48 g of the title compound of Step B. 1H NMR (400 MHz, Me2SO-d6): δ 0.90 (t,3H), 1.60-1.78 (m,2H), 4.30 (t,2H), 8.41 (s,1H), 8.82 (s,1H), 13.55 (s,1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:21]1([CH3:27])[CH:26]=CC=C[CH:22]=1>C(OC(OC(C)(C)C)N(C)C)(C)(C)C.CCOCC>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]([NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:4][C:3]([O:20][C:21]([CH3:22])([CH3:26])[CH3:27])=[O:2])=[CH:8][CH:7]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: Cc1ccccc1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOCC
Product: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C

Procedure:
A solution of 3.50 g of (S)-4-carboxymethyl)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]benzenepropanoic acid methyl ester in 40 mL of dry toluene and 10 mL of dimethylformamide di-t-butyl acetal was heated to a bath temperature of 80° C. for 4 hours. After cooling, the is mixture was diluted with 100 mL of ether and was washed with water and saturated sodium chloride solution and was dried over magnesium sulfate. The residue obtained after filtration and evaporation was chromatographed over 150 g of silica gel, eluting with 20% ethyl acetate-hexane to give 2.663 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino)-4-[2-(1,1-dimethylethoxy)2-oxoethyl]benzenepropanoic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:14][C:5]2[NH:6][C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]#[N:21].O>CN(C=O)C.C(OCC)(=O)C>[C:20]([CH2:19][N:6]1[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:8][C:4]2[CH2:3][C:2]([CH3:1])([CH3:15])[CH2:14][C:5]1=2)#[N:21]
Reactant: CCOC(=O)c1cc2c([nH]1)CC(C)(C)C2
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
A 250-mL single neck round bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 103b)(6.2 g, 30 mmol) in DMF (57 mL). To the solution was added NaH (80% dispersion in mineral oil, 1.26 g, 42.1 mmol). The resulting mixture was stirred at rt for 90 min. After that time, bromoacetonitrile (2.94 mL, 42 mmol) was added. The mixture was stirred for 14 h. After that time, water (100 mL) and ethyl acetate (200 mL) were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to afford a 95% yield (7 g) of 103c.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][CH2:18][N:19](CC)CC.ClCC#N>C1COCC1>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][C:18]#[N:19])[CH2:3][CH2:2]2)=[N:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCN(c2ncnc3ccccc23)CC1
Reaction time: 16 h
Yield: 73.5 %

Procedure:
To a solution of 4-(piperazin-1-yl)quinazoline (1.8 g, 8.3 mmol) in THF (50 mL) was added NEt3 (20 mL, 150 mmol) and chloroacetonitrile (12 mL, 190 mmol) and the reaction was stirred 16 h. The reaction mixture was quenched with 50% saturated aqueous NaHCO3 and extracted with EtOAc (3×200 mL). The combined organics were purified by silica gel chromatography (50% EtOAc/hexanes to 80% EtOAc/hexanes) to yield 55 (1.6 g, 6.1 mmol, 73%) as an viscous yellow oil. 1H NMR: (500 MHz, CDCl3) δ 8.74 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.82-7.55 (m, 1H), 7.54-7.50 (m, 1H), 3.94-3.88 (m, 4H), 3.63 (s, 2H), 2.86-2.81 (m, 4H); LC/MS: (ES+) m/z (M+H)+=254; HPLC Rt=0.71 min., column O.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH3:34][C:35]1[S:39][CH:38]=[N:37][CH:36]=1>O1CCCC1>[Br-:1].[CH3:34][C:35]1[S:39][CH:38]=[N+:37]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:15][CH:14]=3)=[O:11])[CH:4]=2)[CH:36]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(CBr)c2)cc1
Reactant: Cc1cncs1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOc1ccc(NC(=O)Nc2cccc(C[n+]3csc(C)c3)c2)cc1
Product: [Br-]
Yield: 98.6 %

Procedure:
A mixture of 4 g of N-[3-(bromomethyl)phenyl]-N'-[4-(tetradecyloxy)phenyl]urea and 2.3 g of 5-methylthiazole in 60 ml of tetrahydrofuran is refluxed for 4 hours. The solvent is evaporated, toluene added to the residue and evaporated to a residue. The residue is stirred with ether and the solid collected, washed with fresh ether and dried under vacuum to give 4.7 g of the desired product as a white powder, m.p. 65°-168° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:38][N:39]=1
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3s2)CC1

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (265 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 64 mg of 182. MS (Q1) 485.2 (M)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][OH:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.Cl>N1C=CC=CC=1>[S:16]([O:1][CH2:2][C:3]([CH2:8][O:9][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([CH2:6][O:7][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH2:4][O:5][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(CO)(CO)CO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)COS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 48 h
Yield: 90.7 %

Procedure:
A mixture of pentaerythritol (27.20 grams, 199.8 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) and p-toluenesulfonyl chloride (171.0 grams, 897.0 mmol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) in dry pyridine (300 milliliters; obtained from Anachemia) was stirred for 48 hours under nitrogen gas. This mixture was then added to 2 liters of 6 Normal hydrochloric acid. The resulting white precipitate was filtered and washed with methanol. The solid was recrystallized from benzene to afford pure pentaerythritol tetratosylate (136.5 grams, 181.3 mmol, 91 percent yield) as white crystals: mp 155–156° C.; IR (KBr) 3047, 2958, 2926, 1907, 1599, 1468, 1367, 1296, 1174, 1180, 1096, 976, 835, 666, 607, 554 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 8H, 3J=8.2 Hz), 7.36 (d, 8H, 3J=8.2 Hz), 3.82 (s, 8H), 2.47 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 145.86, 131.50, 130.38, 128.15, 65.74, 43.41, 21.90; MS (FAB, 3-nitrobenzyl alcohol) m/e 753; Anal. Calcd for C33H36O12S4: C, 52.64; H, 4.82; S, 17.04. Found: C, 52.98; H, 4.77; S, 17.60.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[ClH:7].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24](O)=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1>ClCl>[ClH:4].[N:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:23]=[C:22]([C:24]([Cl:7])=[O:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(-c2ccncc2)nc2ccccc12
Agent: Cl
Agent: ClCl
Product: O=C(Cl)c1cc(-c2ccncc2)nc2ccccc12
Temperature: -10 °C
Reaction time: 72 h
Yield: 126 %

Procedure:
1.3 ml (10.4 mmol) of oxalyl chloride were dissolved in 60 ml of CH2 Cl2. The solution was cooled at -10° C. and 3.0 g (14.4 mmol) of 2-(4-pyridyl)quinoline-4-carboxylic acid hydrochloride were added portionwise. The reaction mixture was left 72 hours at room temperature and then evaporated to dryness to yield 4.0 g of the title compound, used without further purification.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:30][C:31]([CH3:33])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH:31]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[S:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)(=[O:12])=[O:13])[CH2:25][CH2:26]1)([CH3:33])[CH3:30]
Reactant: CC(C)=O
Reactant: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2ccc(OC3CCNCC3)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)N1CCC(Oc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)CC1
Reaction time: 2 h
Yield: 52 %

Procedure:
A suspension of 3-(1-naphthylsulfonyl)-5-(piperidin-4-yloxy)-1H-indazole (71.2 mg, 0.175 mmol) in 1,2-dichloroethane was treated sequentially with acetone (0.4 mL, 5 mmol) and acetic acid (0.13 mL, 2.3 mmol), stirred for 2 hours, treated portionwise with sodium triacetoxyborohydride (255 mg, 1.20 mmol), stirred for 25 hours at ambient temperatures under nitrogen, diluted with ethyl acetate and washed with 1.0 N sodium hydroxide and brine. The organic phase was treated with methanol and chloroform, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 0.3-1.0% ammonium hydroxide/3.0-10% methanol in chloroform to afford 5-(1-isopropylpiperidin-4-yloxy)-3-(1-naphthylsulfonyl)-1H-indazole as a light orange foam, 40.9 mg (52.0% yield). The foam was dispersed in methanol and chloroform, treated with isopropanolic HCl and concentrated for 12 hours in vacuo to yield the title product as a light orange foam, 37 mg, Mass spectrum (−EI, [M−H]−) m/z 448. 1HNMR (300 MHz, DMSO-d6): δ14.11-14.15 (m*, 1H), 9.82-9.84 (m, 1H), 8.69-8.76 (m, 1H), 8.54-8.58 (m, 1H), 8.27 (d, 1H, J=8.30 Hz), 8.02-8.04 (m, 1H), 7.70-7.75 (m, 1H), 7.54-7.63 (m, 3H), 7.29-7.36 (m*, 1H), 7.07-7.21 (m* and dd*, 1H, J=9.15 Hz and 2.31 Hz), 4.60-4.81 (m*, 1H), 3.40-3.50 (m, 2H), 3.06-3.21 (m*, 3H), 2.10-2.20 (m, 2H), 2.00-2.08 (m, 1H), 1.80-1.95 (m, 1H), 1.22-1.28 ppm (m, 6H). *Conformational isomers due to protonation of tertiary amine.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:19])[CH:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C1CCCCC1>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:19])[CH:11]([NH:18][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2]2
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: Cc1ccc(CNC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
To a solution of amino-phenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (I76) (100 mg, 0.38 mmol) in dry THF (3.84 mL), are added 4-methylbenzaldehyde (68 mL, 0.57 mmol) and AcOH (0.5 mL, 8.73 mmol). The mixture is stirred at RT and sodium triacetoxyborohydride (163 mg, 0.77 mmol) is added. The reaction is stirred at RT for 1.5 hours then cyclohexane is added and the mixture is evaporated to dryness. The crude is purified by flash chromatography (DCM/MeOH/NH4OH=95/5/0.5) to obtain the title compound as a colorless oil (76 mg, 54% yield, mixture of diastereoisomers).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1.[I-:14].[Na+].I>O>[I:14][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([S:12][CH3:13])[N:3]=1
Reactant: CSc1ncc(C(F)(F)F)c(Cl)n1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: O
Product: CSc1ncc(C(F)(F)F)c(I)n1
Reaction time: 48 h
Yield: 56.4 %

Procedure:
4-Chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine (I13) (5.00 g, 21.9 mmol) was placed into a reaction flask then sodium iodide (9.80 g, 65.6 mmol) and hydroiodic acid (58%; 70 mL) were added. The reaction mixture was stirred for 48 hours in darkness then diluted with water (200 mL) where upon a colourless solid precipitated. The precipitate was collected by filtration and was washed with 10% NaHCO3 solution until neutral. The resulting solid was washed with water (100 mL) then suction dried for 2 hours to give the title compound (I14) (3.956 g, 57%) as a pale yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 2.58 (s, 3H). LCMS Method C: rt 6.30 min, m/z 321.0 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1
Reactant: CCOC(=O)CCc1cc(CCNC(=O)OC(C)(C)C)cc(Cc2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1cc(CCN)cc(Cc2cccnc2)c1
Yield: 72.1 %

Procedure:
A solution of ethyl 3-[3-(2-t-butoxycarbonylaminoethyl)-5(3-pyridylmethyl)phenyl]propanoate (Preparation 39; 4.10 g) and trifluoroacetic acid (4.1 ml) in dry dichloromethane (41 ml) was stirred for 6 hours, additional 4.1 ml portions of trifluoroacetic acid being added after 2 and 5 hours. The solution was evaporated under vacuum and the residue basified with aqueous sodium bicarbonate solution. The mixture was extracted several times with dichloromethane and the combined extracts were dried (MgSO4) and evaporated under vacuum. Water (ca 75 ml) was added and this mixture was acidified to pH 4 with glacial acetic acid and then extracted several times with ethyl acetate. The aqueous layer was basified with aqueous ammonia solution (SG 0.880) and extracted several times with dichloromethane. The combined dichloromethane extracts were washed with water, dried (MgSO4) and evaporated under vacuum to give the title compound as an oil (2.24 g); Rf 0.10 (SS 2); δ (CDCl3): 1.07(2H,br), 1.20(3H,t,J=7.1 Hz), 2.56(2H,t,J=7.8 Hz), 2.66(2H,t,J=6.9 Hz), 2.85-2.93(4H,m), 3.90(2H,s), 4.09(2H,q,J=7.1 Hz), 6.84 (2H,s), 6.88(1H,s), 7.16-7.20(1H,m), 7.43(1H,d,J=7.8 Hz), 8.43-8.47(2H,m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>>[CH2:20]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[C:5]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[CH3:17])=[CH:6]1)[CH:19]=[CH2:18]
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Product: C=CCn1cc(C[C@H]2CCCN2C)c2cc(Br)ccc21
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a stirred solution of (R)-5-bromo-3-(1-methyl-2-pyrrolidinylmethyl)-1H-indole (22.5 g, 76.8 mmol) in tetrahydroflran (132 ml) at 0° C. under a nitrogen atmosphere was added potassium tert-butoxide (9.47 g, 84.4 mmol) portionwise, maintaining the temperature below 5° C. Upon completion of the addition, the dark brown slurry was stirred at 0-5° C. for 30 min before allyl bromide (7.3 ml, 84.3 mmol) was added dropwise maintaining the temperature below 5° C. The brown solution was then warmed to ambient temperature over a 1 hr period before being quenched into water (100 ml). The mixture was then extracted with ethyl acetate (3×25 ml) and the combined organic extracts were evaporated in vacuo to give a brown oil. This was purified by flash column chromatography (ethyl acetate:hexane:diethylamine 1:1:0.1 as eluant) to yield the subtitle compound (19.94 g, 78%) as a golden oil.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][C:7]1[NH:11][N:10]([CH3:12])[C:9](=[O:13])[CH:8]=1.Cl[CH:20]([F:22])[F:21]>O.O1CCOCC1>[Cl:3][C:4]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][C:7]1[N:11]([CH:20]([F:22])[F:21])[N:10]([CH3:12])[C:9](=[O:13])[CH:8]=1
Reactant: Cn1[nH]c(Cc2cccc(Cl)c2Cl)cc1=O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(=O)cc(Cc2cccc(Cl)c2Cl)n1C(F)F

Procedure:
A solution of 19 g (0.48 mol) of sodium hydroxide in 165 ml of water was added to a solution of 24.5 g (95.3 mmol) of 5-(2,3-dichlorobenzyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one in 200 ml of dioxane. The mixture was subsequently heated to 60—65° C. and gaseous chlorodifluoromethane was passed through until the starting material had been completely consumed (after about 2 hours). The reaction mixture was then poured into 500 ml of water. The product was extracted with methyl tert-butyl ether. The organic phase was finally dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1:1). Yield: at first 11.5 g of compound Ic.1 and thereafter 5.8 g of compound IIIc.1;