Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Mg]Br.C(O[B:14]1[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]1)(C)C.O>C1COCC1>[CH3:21][C:16]1([CH3:22])[C:17]([CH3:20])([CH3:19])[O:18][B:14]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[O:15]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccccc1[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.25 h

Procedure:
To 200 ml (0.21 mol) of 1.07 M solution of 2-methyl phenylmagnesiumbromide in THF, 49.3 g (0.27 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added at room temperature. The resulting solution was stirred for 15 min at the same temperature, and then 50 ml of water was added. The formed mixture was poured into 500 ml of water, and crude product was extracted with 3×200 ml of ethyl acetate. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. Fractional distillation of the residue in vacuum gave colorless oil, b.p. 81-84° C./3 mmm Hg. Yield 33.1 g (57%). Anal. calc. for C13H19BO2: C, 71.59; H, 8.78. Found: C, 71.78; H, 8.65. 1H NMR (CDCl3): 7.78 (m, 1H, 6-H), 7.33 (m, 1H, 5-H), 7.16-7.19 (m, 2H, 3, 4-H), 2.56 (s, 3H, Me in 2-MeC6H4), 1.36 (s, 12H, Bpin).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3]1)[NH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:10]3=O.[C:29]1([CH3:41])[CH:34]=[CH:33][C:32]([S:35]([N:38]=C=O)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClC(Cl)C>[CH3:22][O:21][C:19]([C:12]1[CH:11]=[C:10]([NH:38][S:35]([C:32]2[CH:33]=[CH:34][C:29]([CH3:41])=[CH:30][CH:31]=2)(=[O:36])=[O:37])[C:9]2[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]3[O:5][C:4]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:3][C:2](=[O:1])[C:7]=3[CH:8]=2)[N:13]=1)=[O:20]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCCc1c2[nH]c(C(=O)OC)cc(=O)c2cc2c(=O)cc(C(=O)OCC)oc12
Solvent: CC(Cl)Cl
Product: CCCc1c2nc(C(=O)OC)cc(NS(=O)(=O)c3ccc(C)cc3)c2cc2c(=O)cc(C(=O)OCC)oc12

Procedure:
Ethyl 6,9-dihydro-4,6-dioxo-8-methoxycarbonyl-10-propyl-4Hpyrano[3,2-g]quinoline-2-carboxylate (38.5 g, 0.1 mol) was suspended in dichloroethane (200 ml) and 4-toluene-sulphonyl isocyanate (15.1 ml; 0.1 mol) added at room temperature. The whole was then refluxed for 16 hours, allowed to cool, and filtered, to give the sub-title compound as brillant yellow cubes, 44.0 g (82%), m.p. 219° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1.ClCCl.O>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[C:17]([C:15]#[N:16])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 82 %

Procedure:
N-Benzylpiperidin-4-one (25 g), ethyl cyanoacetate (16.4 g), glacial acetic acid (6 ml) and ammonium acetate (2.54 g) were heated together in toluene (200 ml), with removal of water using a Dean and Stark apparatus, for 90 minutes. The mixture was cooled, a further amount of toluene (100 ml) added and the solution washed sequentially with water (100 ml) and brine (100 ml) at which point a red oily product precipitated. The phases were separated and the oily product dissolved in dichloromethane. The toluene and dichloromethane solutions were combined and the solvents removed under reduced pressure to give a residue. The residue was dissolved in dichloromethane and washed sequentially with water and saturated aqueous sodium hydrogen carbonate solution before removal of the solvent under reduced pressure. The crude product was chromatographed on silica gel eluting with 98:2, by volume, dichloromethane:methanol to give the title compound (30.8 g) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][C:8]2([CH3:22])[CH3:21])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:21][C:8]1([CH3:22])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccnc1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(c2cccnc2)Nc2ccc(C(=O)O)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (296.0 mg, 1.0 mmol) in methanol (10.0 mL) and tetrahydrofuran (10.0 mL) was added 50% sodium hydroxide in water (1.5 mL). The reaction mixture was stirred at 70° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-pyridin-3-yl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (266.4 mg, 90%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=283.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:12][CH2:13]S(C)(=O)=O)[C:8]1=[O:27].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[C:50]2([OH:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)=[CH:38][CH:37]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:53]2[CH2:54][CH2:55][C:50]([C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)([OH:56])[CH2:51][CH2:52]2)([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[C:8]1=[O:27]
Reactant: OC1(c2nc3ccccc3n2Cc2ccc(F)cc2)CCNCC1
Reactant: COc1cc(CN2CCC(CCS(C)(=O)=O)(Cc3ccc(Cl)c(Cl)c3)C2=O)cc(OC)c1OC
Product: COc1cc(CN2CCC(CCN3CCC(O)(c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(Cl)c(Cl)c3)C2=O)cc(OC)c1OC

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzyl)-3-(3,4-dichloro-phenylmethyl)-3-(2-methanesulfonyl-ethyl)-2-oxo-pyrrolidine and 4-[1-(4-fluoro-benzyl)-1H-benzoimidazol-2-yl]-4-hydroxy-piperidine to give the title compound: Rf=0.60 (silica gel, 10% methanol/ethyl acetate).
Reaction SMILES: [O:1]=[S:2]1(=[O:34])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1.C1COCC1.[Li+].[OH-]>C(Cl)Cl.O.C(O)(=O)C>[O:34]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[C:11]([S:13][CH3:14])=[CH:12][C:7]=2[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:5][C:4]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:28][CH3:29])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(SC)c(OCC(=O)O)cc2S(=O)(=O)C1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 18; 478 mg, 0.95 mmol) was added THF (15 ml), water (3 ml) and LiOH (34 mg, 1.4 mmol). The reaction was then stirred for 1 hour. Then acetic acid (0.2 ml) was added along with water (10 ml) and DCM (10 ml) The aqueous layer was then extracted three times with DCM. The combined organic phases were then dried and concentrated to give the title compound 450 mg (99%). NMR (400 MHz) 0.7–0.9 (m, 6H), 1.0–1.7 (m, 8H), 2.2 (s, 3H), 3.2 (q, 2H), 3.7 (m, 2H), 4.8 (s, 2H), 6.65 (s, 1H), 6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.35 (s, 1H), 8.4 (brs, 1H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:21]3C=CN=CC=3)[CH:16]=2)[C:11]=1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1CC2C(=CC=C(C)C=2)C(=O)C1.[BH4-].[Na+]>CCO>[C:1]([O:5][CH:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:21])[CH:16]=2)[C:11]=1[C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2cc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: Cc1ccc2c(c1)CC(C)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2c(-c3ccc(Cl)cc3)c(C(OC(C)(C)C)C(=O)O)c(C)cc2c1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3,6-dimethylnaphthalen-2-yl)acetic acid (58) was prepared with a route similar to that described for compound 53 of Example 51 beginning with 3,6-dimethyl-3,4-dihydronaphthalen-1(2H)-one (prepared from 1-(3-methylphenyl)propan-2-one) and omitting steps 5 and 6 of Example 50, and steps 2 and 5 of Example 51. Step 3 of Example 51 was replaced by treatment with NaBH4 in EtOH at room temperature to afford racemic material. The title compound was isolated (0.075 g) as a white amorphous powder. LCMS-ESI− (m/z): [M−H]− calcd for C24H24ClO3: 395.14; found: 394.96. 1H-NMR: 400 MHz, (CDCl3) δ: 7.69-7.61 (m, 1H); 7.58 (s, 1H); 7.54 (s, 1H); 7.53-7.46 (m, 2H); 7.30-7.23 (m, 1H); 7.21 (d, J=8.4 Hz, 1H); 7.14 (d, J=8.4 Hz, 1H); 5.27 (s, 2H); 2.56 (s, 3H); 2.48 (s, 3H); 1.01 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.[CH3:15][O-:16].[Na+].O>COCCOC>[NH2:1][C:2]1[CH:7]=[C:6]([O:16][CH3:15])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: C[O-]
Reactant: Nc1cc(Cl)nc(N2CCOCC2)n1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(N)nc(N2CCOCC2)n1
Temperature: 20 °C
Reaction time: 22 h
Yield: 66 %

Procedure:
60.46 g of 4-amino-6-chloro-2-morpholinopyrimidine (described in Chem. Pharm. Bull. 13, 557) are suspended in 190 ml of 1,2-dimethoxyethane and to this suspension are added 35.4 g of sodium methylate. The suspension is subsequently stirred for 22 hours under reflux and then cooled to 20° C. After addition of 180 ml of water the precipitated product is collected by suction and dried in vacuo at 80° C., affording 39.1 g (66% of theory) of 4-amino-6-methoxy-2-morpholinopyrimidine with a melting point of 162° C.-164° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[O:9]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.C1(C)C=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([NH:20][C:19]2[CH:18]=[CH:17][C:16]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:22][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: Clc1cccc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1cccc(Nc2ccc(Oc3ccccc3)cc2)n1
Yield: 77 %

Procedure:
100 mg of 2,6-dichloropyridine, 150 mg of 4-phenoxyaniline, 329 mg of K2CO3, 3 mg of Pd(OAc)2 and 9 mg of BINAP were charged into a microwave vial and 2.5 mL of dry toluene were added. The mixture obtained was treated in the vial analogously to the method as set out in Example 16a. For flash chromatography a solvent mixture of EtOAc:PE=1:10 was used. 6-Chloro-N-(4-phenoxyphenyl)pyridin-2-amine was obtained in the form of yellow crystals.
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[C:23]([OH:29])=[C:22]([CH:30]([CH3:32])[CH3:31])[CH:21]=1)=O)[CH3:11].C(S)(S)C.C(O)C>ClCCl.[Ni].O>[CH2:10]([O:12][C:13](=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:20]1[CH:21]=[C:22]([CH:30]([CH3:32])[CH3:31])[C:23]([OH:29])=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:25]=1)[CH3:11]
Reactant: CCOC(=O)CCCCC(=O)c1cc(C(C)C)c(O)c(C(C)C)c1
Agent: [Ni]
Agent: CC(S)S
Agent: FB(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CCCCCc1cc(C(C)C)c(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boron trifluoride diethyl etherate (4.8 mL, 39 mmol) was added to a mixture of 6-(4-hydroxy-3,5-diisopropyl-phenyl)-6-oxo-hexanoic acid ethyl ester (13.19 g, 39.4 mmol) and ethanedithiol (3.5 mL, 39.3 mmol) in dichloromethane (100 mL), and the resulting deep red mixture was stirred overnight at room temperature. An additional amount of boron trifluoride diethyl etherate (1.2 mL, 10 mmol) was added, and the reaction mixture was stirred an additional 4 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution, and the organic solution was dried over magnesium sulfate, filtered, and concentrated to an orange oil. The oil was chromatographed on silica gel (70-230 mesh) using 19:1, then 9:1, then 83:17 hexanes/ethyl acetate, v/v, as eluant. A mixture of this dithioketal (3.65 g, 8.9 mmol), Raney nickel (41 g of a slurry in water), and ethanol (250 mL) is heated to 50° C. for 2.5 hours under nitrogen. No starting material remained by tlc. The ethanol was decanted from the nickel and the nickel washed and decanted twice with ethanol. The combined ethanol solutions were passed through celite, the ethanol evaporated, and the residue chromatographed on silica gel (70 230 mesh) using 4:1, hexanes/ethyl acetate as eluant. The product was obtained as a yellow oil in two portions, 2.95 g. CI Mass Spectrum: [M+H+ ]+ =320.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:37][CH2:36][C:20]3[NH:21][C:22]4[C:23]([O:28]CC5C=CC=CC=5)=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2]>C(OCC)(=O)C.[Pd]>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:37][CH2:36][C:20]3[NH:21][C:22]4[C:23]([OH:28])=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(OCc5ccccc5)cccc4c3C2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Yield: 43 %

Procedure:
The (1R,2R)-2-(6-Benzyloxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indole-2-carbonyl)-cyclohexanecarboxylic acid (1-cyano-cyclopropyl)-amide in ethyl acetate (15 mL) was hydrogenated over 5% palladium on carbon (10 mg). After an apparent uptake of 5 mL (30 min) the reaction was stopped and a sample taken for LCMS. The catalyst was filtered off and a different batch of catalyst and ethanol (5 mL) were added and the hydrogenation continued. Although there was no further uptake apparent after 3 h the reaction was stopped and LCMS indicated that the reduction had proceeded to the required product. Purified by preparative HPLC (0.5% HCOOH, CH3CN/H2O gradient) to give a white powder (34.7 mg, 43%)
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.CON(C)[C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1>C1COCC1>[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH2:21][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)=[O:36])[CH:18]=[CH:17][N:16]=1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: CSc1nccc(C)n1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CSc1nccc(CC(=O)c2cccc(C(F)(F)F)c2)n1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.9 %

Procedure:
To a solution of diisopropylamine (7.9 mL, 0.056 mole) in THF (100 mL) at -78° C. under argon was added 2.5M N-butyllithium (22.5 mL, 0.056 mole), followed after 5 minutes by a solution of 2-methylthio-4-methylpyrimidine (5.27 g, 0.0376 mole) in THF (20 mL). Upon stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (9.63 g, 0.041 mole) in THF (90 mL) was added. The reaction was allowed to warm to 0° C. and then quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to a solid (11.9 g). Trituration with 10% ether/hexane (100 mL) gave 9.5 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:14]OC)[CH2:9][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=[C:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:17][C:18]2([C:19](=[O:20])[O:21][CH2:22][CH2:23]2)[CH2:14]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1CCOC1=O
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCCC12CCN(Cc1ccccc1)C2
Temperature: 25 °C

Procedure:
A stirred solution of N-benzyl-N-(methoxymethyl)-N-[(trimethylsilyl)methyl]amine (D12, 160 g of 75% purity, assume 0.51 mole) and α-methylene-γ-butyrolactone (D14, 50 g, 0.51 mole) in dichloromethane (11 L) under nitrogen was cooled to 0° C. and then treated with a 1M solution of trifluoroacetic acid in dichloromethane (50ml, 0.05 mole), keeping the temperature below 5° C. The reaction mixture was allowed to warm to room temperature over 2 h, then washed with saturated sodium bicarbonate solution. The aqueous wash was extracted with dichloromethane and the organic solutions then combined, washed with brine, dried (Na2SO4) and concentrated in vacuo to leave a pale yellow oil. This was distilled in vacuo to give the title compound (D15) as a colourless oil (96 g, 81%) b.p. 160°-170° C. at 1 mmHg.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[C:4]([CH3:16])[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][S:25]([NH2:28])(=[O:27])=[O:26])=[CH:20][CH:19]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([CH3:16])[N:3]=[C:2]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][S:25]([NH2:28])(=[O:26])=[O:27])=[CH:20][CH:19]=2)[N:7]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: COc1ccccc1-c1cc(C)nc(Cl)n1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(C)nc(Nc2ccc(CS(N)(=O)=O)cc2)n1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-6-methyl-pyrimidine (0.939 g, 0.004 mol) (Cocuzza, Anthony J. et al., PCT Int. Appl. (1999), WO 9901439 A1, 19990114.), and (4-amino-phenyl)-methanesulfonamide (0.745 g, 0.004 mol) in DMF (12 ml) is stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to give {4-[4-(2-methoxy-phenyl)-6-methyl-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][CH:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CS(=O)(=O)OCC[C@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2c(F)cccc2Cl)C1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1c(F)cccc1Cl)N1CC[C@@](CCN2CCC(N3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (S)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-chloro-6-fluorophenyl)acetyl]pyrrolidine (3.17 g), prepared as described, Supra, is mixed with an equimolar amount of 4-(piperidin-1-yl)piperidine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum an the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[O:4][CH2:3][C@@H:2]1[C:11]1[N:15]=[C:14]([NH:16][C:17]2[N:22]=[CH:21][C:20]([S:23][CH2:24][CH2:25]C(OC)=O)=[CH:19][C:18]=2[O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[S:13][N:12]=1.C[C:39]([O-:42])(C)C.[K+].BrCCOC>C1COCC1>[CH3:39][O:42][CH2:25][CH2:24][S:23][C:20]1[CH:19]=[C:18]([O:30][C:31]2[C:32]([CH3:37])=[N:33][CH:34]=[CH:35][CH:36]=2)[C:17]([NH:16][C:14]2[S:13][N:12]=[C:11]([C@H:2]3[CH2:3][O:4][C:5]4([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]4)[O:1]3)[N:15]=2)=[N:22][CH:21]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Reactant: CC(C)(C)[O-]
Agent: COCCBr
Agent: [K+]
Solvent: C1CCOC1
Product: COCCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 100 %

Procedure:
(S)-Methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (2.0 g, 3.68 mmol) was dissolved in THF (20 mL) and nitrogen was bubbled through the solution for 5 minutes. Potassium 2-methylpropan-2-olate (1M in THF, 11.0 ml, 11.0 mmol) was added and the reaction was stirred at ambient temperature for 1 minute. 1-Bromo-2-methoxyethane (0.518 ml, 5.52 mmol) was added and the reaction was stirred at ambient temperature for 20 minutes. The reaction was partitioned between EtOAc and aqueous NH4Cl, dried, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-N-(5-(2-methoxyethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.9 g, 3.68 mmol, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30].C(N(CC)CC)C>O1CCCC1>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH2:26][CH3:27]
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1ccc(NS(=O)(=O)CCC)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are treated with 116 mg (0.816 mmol) of 1-propanesulfonyl chloride and 87 mg (0.816 mmol) of triethylamine in 15 ml of tetrahydrofuran for 1 hour.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1([CH3:12])[CH2:10][C:9](=[O:11])[O:8][C:6]1=[O:7]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:9](=[O:11])[CH2:10][C:5]([CH3:12])([CH3:4])[C:6]([OH:8])=[O:7]
Reactant: CNC
Reactant: CC1(C)CC(=O)OC1=O
Solvent: C1CCOC1
Product: CN(C)C(=O)CC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of dimethylamine (6.8 g, 150 mmol) in tetrahydrofuran (150 ml) at 0° C. was added dropwise a solution of 2,2-dimethylsuccinic anhydride (4.8 g, 37.5 mmol) in tetrahydrofuran (50 ml) and reaction mixture stirred for about 16 hours at ambient temperature. The solvent was removed in vacuo and the residue was washed with 6N hydrochloric acid (5 ml) and methylene chloride was added to dissolve the precipitate. The solution was washed with saturated aqueous sodium chloride (2×25 ml), dried over magnesium sulfate and concentrated to a pale yellow solid. The solid was dissolved in methylene chloride (20 ml) and the desired product precipitated upon the addition of hexane to yield a colorless solid. mp 119°-121° C.