Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][CH2:30][OH:31])[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>ClCCl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:32]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][CH2:30][O:31][S:41]([CH3:40])(=[O:43])=[O:42])[CH:28]=5)[N:18]4[N:17]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: OCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-ethanol (0.55 g, 1.28 mmol) in dichloromethane (5 ml) was added triethylamine (450 μl, 3.20 mmol) followed by methanesulfonyl chloride (200 μl, 2.56 mmol). The mixture was stirred for 18 hours at room temperature, and partitioned between ethyl acetate and ammonium chloride. The aqueous phase was extracted multiple times with ethyl acetate, and the combined organic phases dried over magnesium sulfate, filtered and concentrated in vacuo to provide a white fluffy solid. No further purification was required. Yield: 0.34 g, 52%; LCMS method: 2, RT: 2.25 min, MI: 512 [M+1].
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:13]1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:27])=O>C1COCC1.CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])[CH2:13]1)[C:5]([Cl:27])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc(OC2CCN(C(=O)N3CCCC3)C2)c(I)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound 34e (166 mg, 0.39 mmol) in THF (4 mL) was added oxalyl dichloride (43 μL, 0.50 mmol) dropwise at 0° C., followed by the addition of 2 drops of DMF. The resulting mixture was stirred at 0° C. for 3 h, warmed to room temperature, and stirred for 18 h. The solvents were removed under reduced pressure. The resultant residue, compound 34f, was dried under reduced pressure for 2 h and used in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=4)(=[O:22])=[O:21])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NCc1ccccn1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1S(=O)(=O)Cl
Solvent: CC#N
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1S(=O)(=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzenesulfonyl chloride (i.e. the product of Step B) (0.2 g, 0.42 mmol) in acetonitrile (20 mL) was added 2-(aminomethyl)pyridine (0.108 mL, 1.05 mmol). The reaction mixture was heated to reflux, and then allowed to stir at ambient temperature for 0.5 h. The mixture was then concentrated to dryness and the crude product was purified by silica gel chromatography using hexane:ethyl acetate (80:20) as eluent. The isolated product was triturated with a mixture of ether and hexane to afford the title product, a compound of the present invention, as a white solid (59 mg), m.p. 57-58° C.
Reaction SMILES: C([Li])(C)(C)C.[Si:6]([C:10]#[CH:11])([CH3:9])([CH3:8])[CH3:7].[C:12]([Si:16]([CH3:23])([CH3:22])[O:17][CH2:18][C@@H:19]1[CH2:21][O:20]1)([CH3:15])([CH3:14])[CH3:13].B(F)(F)F>C1COCC1>[Si:16]([O:17][CH2:18][C@@H:19]([OH:20])[CH2:21][C:11]#[C:10][Si:6]([CH3:9])([CH3:8])[CH3:7])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Reactant: C#C[Si](C)(C)C
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CC#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
tert-Butyl lithium (2 eq) is added to a solution of TMS-acetylene (2 eq) in THF at −78° C. and the reaction mixture stirred for an additional 30 min. (S)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (1 eq) and BF3.EtO2 (2 eq) are added and stirred at −78° C. for 4.5 hours. The reaction is quenched by addition of aqueous ammonium chloride solution and extracted with ethyl acetate (3×). The combined organic layers are washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford (S)-1-(tert-butyldimethylsilyloxy)-5-(trimethylsilyl)pent-4-yn-2-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]([CH3:14])[C:12]#[N:13])[CH:7]=[CH:8][C:9]=1[OH:10]
Reactant: CC(C#N)c1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C#N)c1ccc(O)c(N)c1
Reaction time: 3.8 h
Yield: 52.4 %

Procedure:
2-(3-Nitro-4-hydroxyphenyl) propionitrile (38.4 g., 0.2 mole.) was suspended in absolute ethanol (250 ml.) and hydrogenated at 4 atmospheres pressure and room temperature over 10% palladium on charcoal. Hydrogenation was complete in 3.8 hours. The catalyst was removed by filtration. Evaporation of the filtrate yielded 2-(3-amino-4-hydroxyphenyl) propionitrile (17 g.), m.p. 110°C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: [N-]=[N+]=NCc1cccc2cnccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NCc1cccc2cnccc12
Reaction time: 5 h

Procedure:
To a solution of 0.0282 g (0.15 mmol) 17 in 1 mL EtOAc was added 0.0034 g Pd (10% on C). After 5 h under H2 at atmospheric pressure, the reaction mixture was diluted with 30 mL EtOAc and filtered over celite. The celite was washed with 200 mL EtOAc, and the filtrate was concentrated in vacuo. Purification by flash chromatography (10×160 mm silica gel, 5% (10% NH40H:MeOH):CH2Cl2) yielded 18. 1H NMR (CDCl3, 400 MHz) δ 9.272 (s, 1H, ArH); 8.583 (d, 1H, J=5.94 Hz, ArH); 7.876 (dd, 2H, J=7.18, 11.57 Hz, ArH); 7.583 (t, 1H, J=7.64 Hz, ArH); MS (Electrospray): m/z 159.0 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)[CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]1.CI.[H-].[Na+].N1C2C=CC=CC=2N[CH:37]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O.O>[C:17]([CH:14]1[CH2:13][CH2:12][CH:11]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=2)[C:2]2[N:1]([CH3:37])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH2:16][CH2:15]1)([CH3:18])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(CN(c2nc3ccccc3[nH]2)C2CCC(C(C)(C)C)CC2)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the title compound from Example 1 Step C (0.72 mmol, 300 mg) in 5 mL of THF was added MeI (1 mmol, 67 μL), followed by NaH (1 mmol, 40 mg of 60% dispersion in mineral oil) (exothermic, H2 evolution). After 1 h starting benzimidazole was still present, so the reaction was treated with additional MeI (1 mmol) and NaH (1 mmol). After 1 h the reaction was complete (HPLC A: 2.38). The mixture was concentrated under reduced pressure and the residue was taken up in 6 mL of dioxane. A solution of LiOH (7 mmol, 172 mg) in 2 mL of H2O was added and the resulting mixture was stirred at ambient temperature overnight. The mixture was poured into EtOAc/H2O, and acidified with 2 N HCl until two clear layers formed after agitation. The organic layer was collected and the aqueous layer was washed with EtOAc. The combined organic phase was dried with MgSO4 and concentrated under reduced pressure affording product as a yellow solid. MS (ESI): m/z 420 (M+H). HPLC A: 2.09 min.
Reaction SMILES: C([BH3-])#N.[Na+].[Si:5]([O:12][C@H:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=O)([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[NH2:22][C@H:23]([CH3:37])[CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=1.C(OCC)(=O)C>CO.O>[CH3:36][O:35][C:33]([CH2:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][CH2:24][C@H:23]([NH:22][CH2:14][C@H:13]([O:12][Si:5]([C:8]([CH3:9])([CH3:10])[CH3:11])([CH3:6])[CH3:7])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:37])=[CH:27][CH:28]=1)=[O:34]
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](C=O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
630 mg of sodium cyanoborohydride were added, whilst ice-cooling, to a solution of 1.01 g of (R)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 25) and 750 mg of methyl 4-(2(R)-amino-1-propoxy)phenylacetate (prepared as described in Preparation 27) in 10 ml of absolute methanol, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was mixed with ethyl acetate and water. The organic layer was separated, washed with water and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound.
Reaction SMILES: 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(C)([O-])C.[Na+].[C:53](=[NH:66])([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.Br[C:68]1[CH:69]=[C:70]2[C:74](=[C:75]([F:77])[CH:76]=1)[C:73]([CH3:79])([CH3:78])[CH2:72][CH2:71]2>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:77][C:75]1[CH:76]=[C:68]([N:66]=[C:53]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:69]=[C:70]2[C:74]=1[C:73]([CH3:79])([CH3:78])[CH2:72][CH2:71]2
Reactant: CC1(C)CCc2cc(Br)cc(F)c21
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC1(C)CCc2cc(N=C(c3ccccc3)c3ccccc3)cc(F)c21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Pd2(dba)3 (267 mg, 0.29 mmol), BINAP (363 mg, 0.58 mmol), sodium tert-butoxide (841 mg, 8.75 mmol) and benzophenone imine (1.05 g, 0.98 mL, 5.83 mmol) were added to a solution of the crude 5-bromo-7-fluoro-1,1-dimethylindane in anhydrous toluene (30 mL) at room temperature, and the mixture was stirred at 80° C. for 1 hr under argon atmosphere. To the reaction mixture was added ice water, and the mixture was extracted with ethyl acetate (×2). The organic layer was concentrated under reduced pressure to give crude N-(7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)-1,1-diphenylmethanimine as an orange oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:27]=[CH:26][C:9]2[O:10][CH2:11][C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3[CH:14]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[C:8]=2[CH:7]=1)=[O:5])C.[OH-].[Na+:29]>CO>[Na+:29].[CH3:21][N:18]1[CH2:17][CH2:16][N:15]([CH:14]2[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[CH2:11][O:10][C:9]3[CH:26]=[CH:27][C:6]([C:4]([O-:5])=[O:3])=[CH:7][C:8]2=3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)c1ccc2c(c1)C(N1CCN(C)CC1)c1ccccc1CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C2c3ccccc3COc3ccc(C(=O)[O-])cc32)CC1

Procedure:
A mixture of 3.66 g of 11-(4-methylpiperazino)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid ethyl ester (compound 1) and 0.44 g of sodium hydroxide in 100 ml of 50% aqueous methanol was heated under reflux for one hour. The reaction mixture was concentrated to dryness to obtain 11-(4-methylpiperazino)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid sodium salt as residue. This product was subjected to column chromatography on silica gel using methanol:acetic acid (100:3 v/v) as eluent. Then, the main fraction was concentrated to dryness, and the residue was triturated in dichloromethane to obtain 4.10 g of 11-(4-methylpiperazino)-6,11-dihydrodibenz[b,e]oxepin-2-carboxylic acid diacetate/dihydrate (compound 3) (yield: 83.0%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([NH:51][CH2:52][CH3:53])[CH3:50]>CN(C=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:51]([CH2:52][CH3:53])[CH2:49][CH3:50])=[O:23])[C:17]1=[O:26])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)[C@H](C)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.015 g) in DMF (1 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.015 g), HOBT (0.01 g) and triethylamine (0.007 ml) and the mixture was stirred at room temperature for 30 min. Diethylamine (0.007 ml) was added and the resultant mixture stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by mass directed preparative h.p.l.c. to give the title compound (0.008 g) as a colourless oil.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:28][CH2:27][C@H:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.ClCCCl.FC(F)(F)C(O)=O.O>C1(C)C=CC=CC=1>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[C@H:23]1[CH2:24][CH2:25][C@H:26]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:27][CH2:28]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](NS(C)(=O)=O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CS(=O)(=O)N[C@H]1CC[C@H](c2ccc(O)cc2O)CC1
Temperature: 25 °C

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added trans-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methanesulfonamide (320 mg, 0.57 mmol) and 1,2-dichloroethane (50 ml). To the stirred solution was added trifluoroacetic acid (20 ml) and water (20 ml). The stirred reaction mixture was then heated under reflux for 18 hr and then cooled to room temperature. Toluene (70 ml) was added and the solvent removed in vacuo. Methanol (50 ml) was then added to the residue and the solvent removed under reduced pressure. The resulting oil was purified via flash column chromatography (SiO2, ethyl acetate/petroleum ether, 1:3, 1:2, then 1:1 v/v) to furnish the title product (115 mg, 71%) as a white solid. m/z (ES+) 286 (M+H+); δH(CD3OD) 1.52 (4H, m), 1.89 (2H, m), 2.13 (2H, m), 2.80 (1H, m), 3.00 (3H, s), 3.28 (1H, m), 6.27 (1H, d), 6.29 (1H, dd), 6.92 (1H, d).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=1.Cl.[N:16]1([C:22]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[S:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[S:24]1[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:22]([N:16]2[CH2:17][CH2:18][N:19]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([CH3:14])[CH:5]=3)[CH2:20][CH2:21]2)=[N:23]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)Nc1ccc(CCCl)cc1C
Agent: Cl
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C

Procedure:
Starting from N-[4-(2-Chloro-ethyl)-2-methyl-phenyl]-acetamide (11.96 g, 56.5 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (16.58 g, 73.5 mmol), (N-{4-[2-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-acetamide was prepared according to the general method as outlined in Example 501. The titled product was obtained as an off-white solid, (19.04 g, 48.3 mmol). Yield=85%. 98.8% purity by HPLC; mp 176.5–178.° C.
Reaction SMILES: [Br:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:9]([CH3:10])[CH:8]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(CO)ccc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(COS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of compound 2 (2.0 g, 9.95 mmol), Et3N (6.94 mL, 49.7 mmol), and CH2Cl2 (100 mL) was cooled to 0° C. and treated with methanesulfonyl chloride (1.54 mL, 19.9 mmol). The solution was stirred at room temperature for 3 hours. The volatiles were removed under reduced pressure and the resultant crude product was used without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[C:6]=1[CH3:13].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH2:11][C:7]1[C:6]([CH3:13])=[C:5]([O:4][CH2:3][CH2:2][OH:1])[CH:10]=[CH:9][N:8]=1
Reactant: Cc1c(OCCO)ccnc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(OCCO)ccnc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.9 g of the 4-(2-hydroxyethoxy)-2-hydroxymethyl-3-methylpyridine prepared above was dissolved in 200 ml of dichloromethane to obtain a solution. 24 ml of thionyl chloride was dropwise added to this solution at 0° C. The obtained mixture was stirred at a room temperature for 2 hours and distilled under a reduced pressure to remove the dichloromethane and excess thionyl chloride. A saturated aqueous solution of sodium hydrogencarbonate was added to the residue to obtain a mixture. This mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 10.9 g of 2-chloromethyl-4-(2-hydroxyethoxy)-3-methylpyridine.
Reaction SMILES: N#N.[Br:3][C:4]1[N:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][CH:5]=1.[CH2:13](O)[CH2:14][OH:15].COC(OC)OC.C([O-])([O-])=O.[Na+].[Na+]>>[Br:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:10]2([CH3:11])[O:15][CH2:14][CH2:13][O:12]2)[N:9]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)n1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cccc(Br)n2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(6-bromo-pyridin-2-yl)-ethanone (1880 mg, 9.40 mmol) in ethylene glycol (10.00 mL, 179.32 mmol) was treated with trimethylorthoformate (2.10 mL, 19.16 mmol) followed by LiBF4 (180 mg, 1.88 mmol). The reaction mixture was heated at 95° C. for 5 h. Sat. aq. Na2CO3 was added and the mixture was extracted twice with ether and the combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (50:50 hept-EA)=0.57.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[CH3:12][Si:13]([CH3:40])([CH3:39])[CH2:14][CH2:15][O:16][CH2:17][N:18]1[C:22]2[N:23]=[CH:24][N:25]=[C:26]([C:27]3[CH:28]=[N:29][N:30]([C:32]4([CH2:36][C:37]#[N:38])[CH2:35][NH:34][CH2:33]4)[CH:31]=3)[C:21]=2[CH:20]=[CH:19]1.Cl[C:42]1[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH:56]2[CH2:58][CH2:57]2)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:37]([CH2:36][C:32]1([N:30]2[CH:31]=[C:27]([C:26]3[C:21]4[CH:20]=[CH:19][N:18]([CH2:17][O:16][CH2:15][CH2:14][Si:13]([CH3:39])([CH3:12])[CH3:40])[C:22]=4[N:23]=[CH:24][N:25]=3)[CH:28]=[N:29]2)[CH2:33][N:34]([C:42]2[N:43]=[CH:44][C:45]([C:48]([NH:50][C@@H:51]([CH:56]3[CH2:58][CH2:57]3)[C:52]([F:55])([F:54])[F:53])=[O:49])=[N:46][CH:47]=2)[CH2:35]1)#[N:38]
Reactant: O=C(N[C@@H](C1CC1)C(F)(F)F)c1cnc(Cl)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)N[C@@H](C6CC6)C(F)(F)F)cn5)C4)c3)ncnc21
Temperature: 125 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
N,N-Diisopropylethylamine (0.11 mL, 0.62 mmol) was added to a mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (110 mg, 0.22 mmol) and 5-chloro-N-[(1S)-1-cyclopropyl-2,2,2-trifluoroethyl]pyrazine-2-carboxamide (58 mg, 0.21 mmol) in NMP (2.0 mL). The reaction mixture was stirred at 125° C. for 2 h. The reaction mixture was worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-65%) to afford the desired product (80 mg, 59%). LCMS (M+H)+: m/z=653.2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2].[I:14]I>FC(F)(F)S([O-])(=O)=O.[Ag+]>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([I:14])[CH:13]=1)[O:10][CH2:9][CH2:8][CH2:7]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCCO2
Reactant: II
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Product: CC(=O)c1cc(I)c2c(c1)CCCO2

Procedure:
In accordance with this scheme a 6-bromochroman compound of Formula 2 (see Reaction Scheme 1) is reacted with by tributyl(1-ethoxyvinyl)tin in the presence dichlorobis(triphenylphosphine)palladium(II) under an inert gas (argon) atmosphere in an aprotic neutral solvent, such as tetrahydrofuran (THF), to provide a 6-acetylchroman derivative of Formula 25. The 6-acetylchroman derivative of Formula 25 is then reacted with iodine and silver(I)trifluoromethanesulfonate (AgOTf) to give a 6-acetyl-8-iodochroman derivative of Formula 26. The compound of Formula 26 is reacted with with trimethylsilyl acetylene in triethyl amine under argon atmosphere in the presence of copper(I)iodide and dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh3)2Cl2) to give the 6-acetyl-8-trimethylsilanyl-ethynyl-chroman derivative of Formula 27. The latter reaction is analogous to the conversion of the 8-iodo-substituted chroman compounds of Formula 4 to the 8-trimethylsilanyl-ethynyl-chroman derivatives of Formula 5, as shown in Reaction Scheme 1.