Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:8][CH:7]=1.[CH3:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[Br-:1].[Br-:1].[CH3:17][N+:18]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][N+:18]3([CH3:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:8][CH:7]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: BrCCCCc1ccc(CCCCBr)cc1
Reactant: CN1CCCCC1
Solvent: CCO
Product: C[N+]1(CCCCc2ccc(CCCC[N+]3(C)CCCCC3)cc2)CCCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.1 %

Procedure:
First, 0.35 g of 1,4-bis(4-bromobutyl)benzene and 0.5 g of N-methylpiperidine were dissolved in 5 ml of absolute ethanol, the solution was refluxed for 9 hours, and evaporated under a reduced pressure. To the residue were added acetone and a small amount of ethanol, and the mixture was stirred at a room temperature for 30 minutes. The resulting crystal was filtered, washed with acetone and dried under a reduced pressure to obtain 0.47 g of the title compound as a colorless crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH2:30]Br)=[CH:18][CH:17]=1>CC(C)=O>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][CH:22]=[C:23]2[CH2:26][CH2:27][NH:28][C:29](=[O:32])[CH2:30][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2cccc(CCNC(=O)CBr)c2c1
Reactant: C1COCCN1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc2cccc(CCNC(=O)CN3CCOCC3)c2c1

Procedure:
0.01 mol of morpholine is dissolved under magnetic agitation in 50 ml of acetone, and 0.012 mol of triethylamine and 0.01 mol of N-[2-(7-methoxynaphth-1-yl) ethyl]-2-bromoacetamide are added. The mixture is refluxed for 1 hour under magnetic agitation. The precipitate formed is spun down and the filtrate is evaporated. The residue is taken up in alkaline water, and the precipitate - is spun down, washed, dried and recrystallized in a toluene/cyclohexane mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:20][C:21]1[N:26]=[CH:25][C:24]([CH2:27][CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:28][CH2:27][C:24]3[CH:25]=[N:26][C:21]([CH3:20])=[CH:22][CH:23]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:15][CH2:16][CH2:17][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN2CCCC12
Reaction time: 0.08 h

Procedure:
To a solution of 9-methyl-2,3,4,5,6,10c-hexahydro-1H-3a,6-diaza-cyclopenta[c]fluorene (100 mg, 0.422 mmol) in DMF (1 mL) was added sodium hydride (53 mg, 1.326 mmol). After stirring for 5 min, a solution of toluene-4-sulfonic acid 2-(6-methyl-pyridin-3-yl)-ethyl ester (386 mg, 1.326 mmol) in DMF (1 mL) was added dropwise at 0° C. and the reaction mixture stirred at RT for 6 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured into ice-cold water and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (5×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 9-methyl-6-[2-(6-methyl-pyridin-3-yl)-ethyl]-2,3,4,5,6,10c-hexahydro-1H-3a, 6-diaza-cyclopenta[c]fluorene. 1H NMR, (CDCl3, freebase) δ (ppm): 8.07 (s, 1H), 7.28 (m, 2H), 7.07 (d, 1H), 7.0 (s, 2H), 4.72 (m, 1H), 4.3 (m, 1H), 4.18 (m, 1H), 3.31 (m, 1H), 3.2 (m, 1H), 3.12 (m, 1H), 3.0 (m, 2H), 2.7 (m, 1H), 2.51 (m, 1H), 2.5 (s, 3H), 2.48 (s, 3H), 2.4 (d, 1H), 2.28 (m, 1H), 2.2 (m, 1H), 2.0 (m, 1H), 1.8 (m, 1H). Chiral HPLC provided enantiomers 197a and 197b.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27])=[CH:20][C:19]=1[F:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:25]([N+:26]([O-:28])=[O:27])[CH:24]([C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([F:29])[CH:20]=2)[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.00 g, 4.2 mmol) in CH2Cl2 (5 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-chloro-2-fluoro-4-((E)-2-nitro-vinyl)-benzene (0.68 g, 3.37 mmol) and trifluoroacetic acid (30 ul) in CH2Cl2 (5 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:4) afforded 0.78 g (55%) of the title compound as a colorless oil. ES-MS m/e: 335.2 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1C(N=[N+]=[N-])=O.[CH:12]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]2[C:30]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:29]([O:40][CH2:41][C:42]#[C:43][CH2:44][OH:45])[N:28]=[C:27]([C:46]3[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=3)[N:26]=2)(=[O:23])=[O:22])=[N:19][CH:20]=1)([CH3:14])[CH3:13].C[N:53]([CH:55]=[O:56])C>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH:12]([C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]2[N:26]=[C:27]([C:46]3[CH:47]=[CH:48][N:49]=[CH:50][CH:51]=3)[N:28]=[C:29]([O:40][CH2:41][C:42]#[C:43][CH2:44][O:45][C:55](=[O:56])[NH:53][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:30]=2[O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])(=[O:22])=[O:23])=[N:19][CH:20]=1)([CH3:14])[CH3:13]
Reactant: [N-]=[N+]=NC(=O)c1ccccn1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCC#CCO
Reactant: CN(C)C=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)C)cn2)nc(-c2ccncc2)nc1OCC#CCOC(=O)Nc1ccccn1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A solution of 50 mg of 2-picolinic acid azide (prepared from 2-picolinic acid according to Chem. Pharm. Bull. 25 (1977) 1651-1657) and 10 mg of DMAP in 8 ml of chloroform was stirred for 1 h at 75° C. 50 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide (Example 1g) followed by 3 ml of DMF was added and the resulting clear solution was stirred for 16 h at 75° C. The mixture was diluted with 75 ml of ethyl acetate and washed with 50 ml of 10% aqueous citric acid followed by 50 ml of water. The organic layer was evaporated and the crude product was purified by chromatography on prep. tlc-plates with dichlormethane:methanol 10:1 to give 41 mg of 2-pyridinyl-carbamic acid 4-[6-(5-isopropyl-pyridine-2-sulfonylamino)-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yloxy]-but-2-ynyl ester as a white solid. LC-MS: tR=4.74 min, [M+1]+=682.47, [M−1]−=680.41.
Reaction SMILES: [CH2:1]([Hg:6][CH2:7][CH2:8][CH2:9][CH:10]=C)[CH2:2][CH2:3][CH:4]=C.C([Mg]Br)CCC=C.BrCCCC=C.[Mg]>O1CCCC1.O>[CH2:1]([Hg:6][CH2:7][CH2:8][CH:9]=[CH2:10])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC[Hg]CCCC=C
Agent: C=CCCCBr
Agent: C=CCCC[Mg]Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: C=CCC[Hg]CCC=C
Temperature: 60 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Preparation of bis(4-pentenyl)mercury: To a solution of 4-pentenyl magnesium bromide, prepared from 25 g of 1-bromo-4-pentene (169 mmole) and 5 g of magnesium (208 mmole) in 40 mL of tetrahydrofuran, was added dropwise at 50° C. with stirring a solution of 25.2 g of mercuric chloride (93 mmole) in 50 mL of tetrahydrofuran. After stirring for 2 hours at 60° C., the reaction mixture was hydrolyzed with water at 0°-5° C. The organic layer was separated from aqueous layer; the product was distilled to give bis-3-butenyl mercury in 67% yield. The identity of the compound was confirmed by gas chromatography and 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.CS(O[CH2:21][C:22]1(CO)[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)(=O)=O>C(#N)C>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:21][CH:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)(COS(C)(=O)=O)C1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Product: N
Yield: 76.1 %

Procedure:
To a solution of 4-(3,4-dichlorophenoxy)piperidine (WO 01/77101; 9.22 g) dissolved in acetonitrile (60 ml) was added the product of Step (a) (5.53 g). The mixture was refluxed for 12 hrs and the solvents were evaporated. Purification by flash chromatography eluting with dichloromethane:methanol:NH3 (aq) (2:97.9:0.1) gave the sub-title compound as an oil (5.76 g).
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH2:40])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:42](=O)[CH:43]([CH3:45])[CH3:44].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH:1]1([O:6][C:7](=[O:41])[C@@H:8]([NH:40][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([C:16]([O:22][C:23]4[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:37])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[CH:25][CH:24]=4)=[CH:17][CH:18]=[N:19]3)=[CH:14][C:13]=2[O:38][CH3:39])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)C=O
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](N)C(=O)OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc2c(Oc3ccc(NC(=O)c4ccccc4)cc3)ccnc2cc1OCC[C@H](NCC(C)C)C(=O)OC1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To (S)-2-Amino-4-[4-(4-benzoylamino-phenoxy)-6-methoxy-quinolin-7-yloxy]-butyric acid cyclopentyl ester (37 mg, 0.066 mmol) in anhydrous methanol (1 ml) were added 100 μL of a 1 M solution of isobutyraldehyde in methanol and 1 drop of acetic acid. The reaction mixture was stirred at room temperature for 3 hours. Sodium cyanoborohydride (10.3 mg, 0.165 mmol) was then added and the reaction was left stirring 4 hours at room temperature, prior to concentration under vacuum. Purification by preparative HPLC afforded the title compound as a di-TFA salt (40 mg, 72% yield).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]([F:20])[CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[N:21]([CH:6]1[CH2:11][CH2:10][CH:9]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH:8]([F:20])[CH2:7]1)=[N+:22]=[N-:23]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(OS(C)(=O)=O)CC1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(N=[N+]=[N-])CC1F
Temperature: 100 °C

Procedure:
To a stirred solution of 4-{[tert-butyl(dimethyl)silyl]oxy}-3-fluorocyclohexyl methanesulfonate (570 mg, 1.75 mmol) in DMF (10 mL) was added sodium azide (340 mg, 5.24 mmol). The reaction mixture was heated to 100° C. overnight, diluted with EtOAc, and washed with water. The organic layer was dried, concentrated, and purified by flash chromatography to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:18])[CH2:16][CH3:17])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Br:19]Br.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.Br.C(O)(=O)C>[Br:19][CH:16]([CH3:17])[C:15]([C:5]1[CH:6]=[CH:7][C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:18]
Reactant: CCC(=O)c1ccc(-c2ccccn2)c(OC)c1
Reactant: BrBr
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: COc1cc(C(=O)C(C)Br)ccc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one (120 mg, 0.5 mmol) in benzene (1 mL) and 30% HBr/Acetic acid (1 mL) was cooled to 0° C. and was treated with a solution of bromine (0.024 mL, 0.5 mmol) in benzene (0.5 mL) over 1 h. The reaction was stirred for an additional 30 min, then poured into an iced solution of saturated aqueous NaHCO3 (100 mL), and the product was extracted into ethyl acetate (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated to afford 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)propan-1-one.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH3:9])[C:6]=1[CH2:7]O.[BrH:10].[C:11]1([P:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[Br-:10].[CH3:1][C:2]1[O:3][CH:4]=[C:5]([CH3:9])[C:6]=1[CH2:7][P+:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Br
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1coc(C)c1CO
Solvent: ClCCl
Product: Cc1coc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of 2,4-dimethyl-3-hydroxymethylfuran (11 g.) in dichlormethane (25 ml.) was added to a cooled slurry of triphenylphosphine hydrobromide (34 g.) in dichloromethane to give a clear solution. After standing a further 30 minutes at room temperature the bulk of the solvent was distilled off and the residue was crystallized from a 1:4 parts by volume mixture of methanol and ethylacetate to yield a buff colored solid (27.2 g.) of (2,4-dimethyl-3-furyl)methyl triphenylphosphonium bromide, m.p. 248°-249°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:44]1([CH2:50][CH:51]([N:54]2[CH:58]=[C:57]([C:59]3[C:60]4[CH:67]=[CH:66][N:65](COCC[Si](C)(C)C)[C:61]=4[N:62]=[CH:63][N:64]=3)[CH:56]=[N:55]2)[CH2:52][CH3:53])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1COCC1>[N:62]1[C:61]2[NH:65][CH:66]=[CH:67][C:60]=2[C:59]([C:57]2[CH:56]=[N:55][N:54]([CH:51]([CH2:52][CH3:53])[CH2:50][N:44]3[CH2:49][CH2:48][N:47]([C:4]([C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[OH:1])=[O:6])[CH2:46][CH2:45]3)[CH:58]=2)=[N:64][CH:63]=1
Reactant: CCC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: O=C(O)c1ccccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(CN1CCN(C(=O)c2ccccc2O)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxybenzoic acid (0.0045 g, 0.033 mmol) in tetrahydrofuran (0.5 mL, 6 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.012 g, 0.033 mmol) and N,N-diisopropylethylamine (5.7 uL, 0.033 mmol) and mixed for 1 hour until dissolution. The reaction was stirred overnight, then 4-{1-[1-(piperazin-1-ylmethyl)propyl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.010 g, 0.022 mmol from step 4 in example 115 and 0.5 mL THF were added. After 0.5 hour, the reaction was purified by LCMS (pH 10) to give 14 mg white solid which was stirred in 1 mL MeOH and 50 microL EDA for 2 hours. The reaction was purified by LCMS (pH 10) to give 2.2 mg white solid. 1H NMR (400 MHz, DMSO): δ 8.64 (1H, s); 8.6 (1H, s); 8.22 (1H, s); 7.55 (1H, d); 7.35 (1H, m); 6.99 (1H, m); 6.93 (1H, m); 688 (1H, m); 6.75 (1H, m); 4.39 (1H, m); 3.5-2.2 (10H, br); 1.78 (2H, m); 0.65 (3H, t). LCMS (M+1); 446.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41].O>ClCCl>[C:40]([NH:1][CH2:2][C@@H:3]([C@@H:5]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:6][C@H:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH3:25])[CH:13]=1)[CH:8]([CH3:10])[CH3:9])[OH:4])(=[O:42])[CH3:41]
Reactant: CC(=O)OC(C)=O
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)ccc1OC
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(C)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The solution of 0.040 g of tert-butyl {1(S)-(2-amino-1(S)-hydroxyethyl)-3(S)-[4-methoxy-3-(3-methoxypropoxy)benzyl]-4-methylpentyl}carbamate in 2 ml of dichloromethane is admixed successively with 0.007 ml of pyridine and 0.011 ml of acetic anhydride and stirred at room temperature over 1 hour. The reaction solution is admixed with water and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with 1M HCl, water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained from the residue by means of flash chromatography (SiO2 60F) as a colourless oil. Rf=0.37 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=17.25 (gradient II).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCOc4ccccc4)CC3)noc2c1
Yield: 47 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (4.0 g, 18.2 mmol), K2CO3 (3.0 g, 21.8 mmol), KI (100 mg), 3-chloropropoxybenzene (3.4 g, 20.0 mmol), and acetonitrile was stirred at reflux under nitrogen for 30 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried with MgSO4 and concentrated to afford 6.2 g of a damp, beige solid. The compound was recrystallized twice from ethanol to yield (47%) of 6-fluoro-3-[1-(3-phenoxypropyl)-4-piperidinyl]-1,2-benzisoxazole as a light beige solid, m.p.=78°-80° C.
Reaction SMILES: Cl.CN.[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]=O)[CH:26]=2)=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].[C:33]([BH3-])#[N:34].[Na+]>CO>[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][NH:34][CH3:33])[CH:26]=2)=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCOC(=O)[C@H](Cc1ccc(-c2cccc(C=O)c2)cc1)NC(=O)OC(C)(C)C
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)[C@H](Cc1ccc(-c2cccc(CNC)c2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
21.2 g (314 mmol) of methylamine hydrochloride are introduced into a solution containing 25 g (63.0 mmol) of ethyl (S)-2-tert-butoxycarbonylamino-3-(3′-formylbiphenyl-4-yl)propionate in 200 ml of methanol. After stirring for 30 min at ambient temperature, 6.0 g (95.4 mmol) of sodium cyanoborohydride are added portionwise. The reaction medium is stirred for 16 h and the solvents are evaporated off. The residue is dissolved in ethyl acetate, and the organic phase is washed with water and then dried over magnesium sulfate and concentrated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][OH:10].[CH3:11][S:12](Cl)(=[O:14])=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][CH2:9][O:10][S:12]([CH3:11])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCOc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
2-(Pyridin-2-yloxy)-ethanol (100 mg, 0.72 mmol) was dissolved in DCM (2 mL) and MsCl (72 μL, 0.94 mmol) and DIPEA (192 μL, 1.08 mmol) were added. The mixture was stirred at rt overnight, diluted with EtOAc, washed with water, sat. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford 114 mg methanesulfonic acid 2-(pyridin-2-yloxy)-ethyl ester which was used without further purification for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16][CH3:17])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1.Cl>C1COCC1.CN1C(=O)N(C)CCC1>[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:7]2[CH3:12])=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Reactant: BrCc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: 0 °C
Yield: 48 %

Procedure:
To a solution of ester from Step 1 (13.8 g, 59 mmol) in THF (300 mL) and DMPU (40 mL) at -78° C. was added KHMDS solution (0.64M/toluene, 95 mL, 60 mmol). The reaction mixture was warmed to 0° C. and was then recooled to -78° C., at which point a solution of 4-bromobenzyl bromide (17.0 g, 68 mmol) in THF (80 mL) was added via double-tipped needle. The reaction was allowed to warm to r.t., and was then poured into 1M HCl (500 mL). The product was extracted with Et2O and the organic phase was washed with H2O and brine. After drying (MgSO4), filtration, and removal of solvent, the crude product was purified by flash chromatography (1:20 EtOAc/toluene). The resulting prodeuct was recrystallized from CH2Cl2 /hexane to give 11.4 g of the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1OCC[C@H]2N.Cl[C:14]1[N:19]=C(Cl)C([N+]([O-])=O)=C[N:15]=1.CCN(C(C)C)C(C)C.Cl[C:34]1[N:39]=[C:38]([NH:40][C@H:41]2[C:50]3[C:45](=[C:46]([F:51])[CH:47]=[CH:48][CH:49]=3)[O:44][CH2:43][CH2:42]2)[C:37]([N+:52]([O-:54])=[O:53])=[CH:36][N:35]=1>C1COCC1>[N:15]1([C:34]2[N:39]=[C:38]([NH:40][C@H:41]3[C:50]4[C:45](=[C:46]([F:51])[CH:47]=[CH:48][CH:49]=4)[O:44][CH2:43][CH2:42]3)[C:37]([N+:52]([O-:54])=[O:53])=[CH:36][N:35]=2)[C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:11]=2[N:19]=[CH:14]1
Reactant: N[C@@H]1CCOc2c(F)cccc21
Reactant: O=[N+]([O-])c1cnc(Cl)nc1N[C@@H]1CCOc2c(F)cccc21
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(-n2cnc3ccccc32)nc1N[C@@H]1CCOc2c(F)cccc21
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
(R)-8-Fluorochroman-4-amine (60 mg) was added to a solution of 2,4-dichloro-5-nitropyrimidine (70 mg) and DIEA (0.14 mL) in THF (5 mL) at −78° C. The reaction mixture was stirred for a further 15 min at −78° C. then removed from the cold bath and allowed to warm to RT. A one molar solution of the sodium salt of benzimidazole (0.7 ml, stock solution prepared via the addition of sodium hydride to a benzimidazole solution in THF) was added to the reaction intermediate ((R)-2-chloro-N-(8-fluorochroman-4-yl)-5-nitropyrimidin-4-amine) and the resulting mixture was stirred at RT overnight. Purification via column chromatography (elution with MeOH/DCM) gave the titled compound (120 mg), MH+=407.