Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][NH:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:23](=O)[CH2:24][CH2:25][CH:26]=[CH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:27]([N:16]1[C:10]2[C:11](=[N:12][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[C:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:9]=2)[CH2:13][CH2:14][CH2:15]1)[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: C=CCCC=O
Reactant: c1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: C=CCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,3-diphenyl-5,6,7,8-tetrahydropyrido[3,2-b]pyrazine (Ex. 4.1 step 1) (2 g, 6.96 mmol) in DCE (35 ml) was added pent-4-enal (2.061 ml, 20.88 mmol) and the mixture was stirred at RT overnight. A further portion of sodium triacetoxyborohydride (4.43 g, 20.88 mmol) was added and the mixture was stirred at RT for 2.5 hours under an atmosphere of nitrogen. Water was added and the mixture was extracted with EtOAc (3×60 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:14][CH:15]=[CH2:16])[C:6]([OH:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH:1]([C:3]1[CH:4]=[C:5]([CH2:14][CH:15]=[CH2:16])[C:6]([O:13][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2]
Reactant: C=CCc1cc(C=O)cc(C(=O)OC)c1O
Reactant: CC(C)(C)OC(=O)CBr
Product: C=CCc1cc(C=O)cc(C(=O)OC)c1OCC(=O)OC(C)(C)C

Procedure:
Phenol 36b was alkylated with t-butyl bromoacetate the usual way to give a yellow oil (quant.). 1H-NMR (300 MHz, CDCl3): 9.94 (s, 1H), 8.21 (d, 1H, J=2 Hz), 7.90 (d, 1H, J=9 Hz), 6.05-5.92 (m, 1H), 5.15-5.05 (m, 2H), 4.51 (s, 2H), 3.93 (s, 3H), 3.61 (br d, 2H, J=7 Hz), 1.49 (s, 9H). Anal. Calc'd for C18H22O6 : C, 64.66; H, 6.63; Found: C, 64.54; H, 6.62.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:33]3[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]3)=[CH:8][C:7]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([F:28])[CH:21]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(CCCOS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1F
Product: COc1ccc(-c2cc(CCCN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Yield: 62 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 62.0%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=[CH:12]2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:20]1([CH2:26][CH2:27][NH2:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:26][CH2:27][NH:28][C:5]2[N:10]=[C:9]([N:11]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[N:13]=[CH:12]3)[CH:8]=[CH:7][N:6]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: CS(=O)(=O)c1nccc(-n2cnc3ccccc32)n1
Product: c1ccc(CCNc2nccc(-n3cnc4ccccc43)n2)cc1

Procedure:
2-Methanesulfonyl-4-[benzimidazol-1-yl]pyrimidine was reacted with 2-phenylethylamine according to the procedure described in EXAMPLE 1, Step C to afford the title compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)(O)=[O:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([NH:34][C:1]([CH2:4][C:5]1[C:9]2[C:10]([C:16](=[O:26])[CH2:17][C:18]3[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:25])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH:6]=1)=[O:2])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)O)coc12
Product: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)c2c(CC(=O)NCc3ccccc3)coc12
Yield: 29 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 151 (0.30 g) obtained in Example 151 and benzylamine (0.13 ml) to give Compound 155 (0.11 g, 29%) as white crystals.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[CH2:20][O:19][C:18]2=[O:29])[CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C.[O:39]=[C:40]1[CH2:45][O:44][C:43]2[CH:46]=[CH:47][C:48]([CH:50]=O)=[N:49][C:42]=2[NH:41]1.C([BH3-])#N.[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]2[CH2:20][O:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][CH2:50][C:48]4[CH:47]=[CH:46][C:43]5[O:44][CH2:45][C:40](=[O:39])[NH:41][C:42]=5[N:49]=4)[CH2:14][CH2:13]3)[C:22]=2[CH:23]=1
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)OC2
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)OC2

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-1,4-dihydro-2H-3,1-benzoxazin-2-one trifluoro acetate (Intermediate 106) (324 mg, 0.78 mmol) was converted to the free base using N,N-diisopropylethylamine for 30 minutes and reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (153 mg, 0.86 mmol) and sodium cyanoborohydride (98 mg, 1.56 mmol) as described under Example 21. The reaction mixture was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (9:1) gave the free base of the title compound as a colorless foam. The free base was taken up in 1,4 dioxane (2 mL), followed by addition of 4M HCl in 1,4-dioxane (0.30 mL). The resulting precipitate was collected by filtration and gave 75 mg (48%) of the bis-hydrochloride salt of the product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:16]3[CH:25]=[C:24]4[C:19]([N:20]=[CH:21][C:22](=O)[NH:23]4)=[CH:18][CH:17]=3)=[C:10]3[CH2:15][CH2:14][CH2:13][N:11]3[N:12]=2)[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[Cl:29][C:22]1[CH:21]=[N:20][C:19]2[C:24](=[CH:25][C:16]([C:9]3[C:8]([C:6]4[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)=[N:12][N:11]4[CH2:13][CH2:14][CH2:15][C:10]=34)=[CH:17][CH:18]=2)[N:23]=1
Reactant: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(=O)[nH]c4c2)CCC3)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(Cl)nc4c2)CCC3)n1
Yield: 86 %

Procedure:
Dissolve 7-[2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-1H-quinoxalin-2-one (Example 55b; 200 mg, 0.6 mmol) in phosphorus oxychloride (20 mL). Reflux the solution for 30 min. Evaporate in vacuo. Dissolve the residue in 3:1 chloroform/isopropyl alcohol (100 mL) and wash the solution with 5% aqueous ammonia solution, brine and water. Dry the organic phase over sodium sulfate. Filter and evaporate the solvents in vacuo to give the target product as a yellow solid 180 mg (86%). MS (electrospray, m/z) 362.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:31])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([Br:31])[N:11]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccccc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 103(a) from 2,3-dibromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 517 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:28][CH2:27][NH:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[NH:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH2:34][N:26]1[CH2:27][CH2:28][CH:24]([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)=[N:15]2)[CH2:25]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNC1
Reactant: O=Cc1ncc[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCN(Cc2ncc[nH]2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.4 %

Procedure:
3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 5.81 mmol), 1H-2-imidazolecarbaldehyde (77 mg, 0.806 mmol), sodium triacetoxyborohydride (113 mg, 0.537 mmol) and glacial acetic acid (48 mg, 0.806 mmol) were mixed with 1,2-dichloroethane (4 mL). The reaction mixture was stirred at room temperature for 6 hours and saturated sodium bicarbonate solution was added to adjust the pH to about 9. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10) as mobile phase to give 1-[1-(1H-2-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 83%). 1H NMR (DMSO-d6) δ 2.33 (m, 2H), 2.81 (m, 4H), 3.15 (m, 1H), 3.69 (s, 2H), 5.38 (m, 1H), 6.90 (s, 2H), 7.15 (m, 5H), 7.44 (m, 2H), 7.66 (m, 2H), 8.24 (s, 1H). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.): MH+ 453.4, Rt=2.17 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16](C)C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20]N>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:20][N:16]=[CH:15][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]ncc2C1
Temperature: 25 °C

Procedure:
To a solution of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). The solution was heated to reflux, immediately allowed to cool to room temperature, and concentrated to give 1.4 g (63%) which was used without purification. Mass spec.: 224.11 (MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:20]2([CH2:19][N:6]3[C:7]4[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=4[C:4]4[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]3=4)[O:21][CH2:22][CH2:23][O:24]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Fc1ccc(C2(CBr)OCCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccc(F)cc3)OCCO2)CCN(C)C1
Temperature: 100 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4.6 g, 23 mmol) was dissolved in 35 mL of NMP. Sodium hydride (1.93 g, 48.3 mmol) was added at RT under nitrogen atmosphere. 2-Bromomethyl-2-(4-fluorophenyl)-1,3-dioxolane (6 g, 23 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH:DCM.
Reaction SMILES: [CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42].CCO>CC(O)C>[CH3:1][C:2]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:3]=1[O:4][CH2:5][C@H:6]([OH:35])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[C:10]=1[C:16]1[NH:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:21][N:22]([CH:29]4[CH2:30][CH2:31][N:32]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:33][CH2:34]4)[C:23](=[O:28])[C:24]=3[CH:25]=2)[N:17]=1
Reactant: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCNCC2)C4)c(C)c1
Reactant: C=CS(C)(=O)=O
Solvent: CC(C)O
Solvent: CCO
Product: Cc1ccc(OC[C@H](O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(CCS(C)(=O)=O)CC2)C4)c(C)c1
Temperature: 100 °C
Yield: 77.6 %

Procedure:
A mixture of 2-{4-[(R)-3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-piperidin-4-yl-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (3.04 g, 5.6 mmol) and methyl vinyl sulfone (5.94 g, 56 mmol) in a mixed solvent of EtOH (70.0 mL) and 2-propanol (70.0 mL) was heated at 100° C. for 22 h and then evaporated. Chromatography of the residue with CH2Cl2/MeOH/28% aqueous NH4OH (190:10:1) afforded title compound (2.82 g, 78%). 1H NMR (DMSO-d6) δ 1.68-1.85 (4H), 2.15 (m, 2H), 2.18 (s, 3H, CH3), 2.21 (s, 3H, CH3), 2.75 (m, 2H), 3.05 (m, 2H), 3.08 (s, 3H, CH3), 3.54 (m, 1H), 3.70 (m, 1H), 3.93-4.19 (4H), 4.43 (s, 1H), 4.47 (s, 1H), 5.48 (d, J=6 Hz, 0.5H, NH), 5.53 (d, J=6 Hz, 0.5H, NH), 6.20 (m, 1H), 6.81 (m, 1H), 6.90-6.99 (2H), 7.31-7.37 (1.5H), 7.67 (s, 0.5H), 7.80 (s, 0.5H), 7.94 (s, 0.5H), 11.14 (br d, J=6 Hz, 1H, NH), 11.22 (br d, J=6 Hz, 1H, NH); ESI-MS m/z 649.5 (MH+); Anal. Calcd for C33H40N6O6S: C, 61.09; H, 6.21; N, 12.95; S, 4.94. Found: C, 60.85; H, 6.17; N, 12.87; S, 4.85.
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Cl:12][C:13]1[CH:18]=[N:17][CH:16]=[C:15](Cl)[N:14]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:11][C@H:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:16]=[N:17][CH:18]=1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(N[C@@H]2CCCc3ccccc32)n1
Yield: 73.7 %

Procedure:
In a procedure analogous to Example 1, reaction of (1R)-1,2,3,4-tetrahydronaphthalen-1-amine (441 mg, 3.0 mmol) and 2,6-dichloropyrazine (0.4055 g, 2.72 mmol) furnished the product (521 mg, 74%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([CH:19]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([CH2:19][N:25]2[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC1CN(Cc2ccccc2)CC1c1ccccc1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: OC1CCN(CC2CN(Cc3ccccc3)CC2c2ccccc2)CC1
Yield: 52.7 %

Procedure:
The title compound was prepared from 500 mg of 1-Benzyl-3-(SR)-formyl-4-(SR)-phenylpyrrolidine, 196 mg of 4-hydroxypiperidine and 597 mg of sodium triacetoxyborohydride using a procedure analogous to that described in Example 9, Step B to provide 348 mg of the title compound. RF : 0.16 (5% MeOH in CH2Cl3). 1H NMR (300 MHz, CDCl3): δ1.35-1.54 (m, 2H), 1.69-1.83 (m, 2H), 1.93-2.05 (m, 2H), 2.36-2.71 (m, 7H), 3.89-3.01 (m, 3H), 3.55-3.72 (m, 3H), 7.14-7.38 (m, 10H). Mass Spectrum (NH3 -CI): 351.3 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:36].CO>C(Cl)Cl>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2F)c(-c2ccnc(N)n2)s1
Temperature: 90 °C

Procedure:
A suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (196 mg, 0.364 mmol) and ammonia in methanol 7M (8 ml, 56.0 mmol) was heated in a sealed tube to 90° C. for 24 h. The reaction was diluted with DCM and added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAc:MeOH)]. The clean fractions were concentrated to yield the crude product. The crude product was repurified by reverse phase HPLC (a gradient of acetonitrile:water with 0.1% TFA in both). The combined clean fractions were concentrated then partitioned between DCM and saturated NaHCO3. The DCM layer was separated and dried over Na2SO4. The title compound, N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide was obtained (94 mg, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (s, 1 H), 7.93 (d, J=5.2 Hz, 1 H), 7.55-7.70 (m, 1 H), 7.35-7.43 (m, 1 H), 7.31 (t, J=6.3 Hz, 1 H), 7.14-7.27 (m, 3 H), 6.70 (s, 2 H), 5.79 (d, J=5.13 Hz, 1 H), 1.35 (s, 9 H). MS (ESI): 519.9 [M+H]+.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[N:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:12][N:13]([S:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C:14](F)=[O:15]>>[CH3:12][N:13]([S:17][N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[C:14]([O:2][N:1]=[C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[N:7][CH2:6][CH2:5][S:4]1)=[O:15]
Reactant: CN(SN1CCOCC1)C(=O)F
Reactant: CC(C)C1=NCCSC1=NO
Product: CC(C)C1=NCCSC1=NOC(=O)N(C)SN1CCOCC1

Procedure:
2-Oxo-5,6-dihydro-3-isopropyl-2H-1,4-thiazine oxime is reacted with N-methyl-N-morpholinosulphenylcarbamoyl fluoride as described in Example 25 to yield 2-oxo-5,6-dihydro-3-isopropyl-2H-1,4-thiazine O-(N-methyl-N-morpholinosulphenylcarbamoyl)oxime, m.p. 127°-128.5° C.
Reaction SMILES: COC(=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH2:73]([O:75][C:76](=[O:80])[CH2:77]CN)[CH3:74]>CN(C)C=O>[CH2:73]([O:75][C:76](=[O:80])[CH2:77][CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH3:74]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: CCOC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
To a solution of 0.18 g (0.37 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 2 mL N,N-dimethylformamide were added 0.148 g (0.39 mmol) 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.25 mL (1.49 mmol) N,N-diisopropylethylamine. To the light brown solution 0.060 g (0.39 mmol) beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2) was added and the solution was stirred at room temperature for 3.5 hours. The solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed twice with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) with a gradient of n-heptane:ethyl acetate (100:0 to 0:100) to afford 0.185 g (85%) of the title compound as a light brown foam. MS (ESI): m/z=583.15 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CS(C)=O>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([NH:33][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: NCc1ccccc1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(NCc4ccccc4)nc32)c(=O)[nH]c1=O
Temperature: 60 °C

Procedure:
A mixture of the product from example 44 step (viii) (0.25 g) and benzylamine (0.14 ml) in dry 1,4-dioxane (3 ml) were heated at 60° C. for 36 h. After this time benzylamine (0.14 ml) and dry dimethylsulphoxide (2 ml) were added and the mixture was heated at 60° C. for a further 72 h. The solvent was removed under reduced pressure. Purification was by trituration with diethyl ether and water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[C:4]=1[NH:13][C:14]([CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(O)=O)=[O:15].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:38]([NH:52][NH2:53])(=[O:51])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C1COCC1>[O:15]=[C:14]([NH:13][C:4]1[C:5]([O:11][CH3:12])=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[CH:16]([CH:39]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:38]([NH:52][NH2:53])=[O:51])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCCCCCCCCCCC(=O)NN
Reactant: COc1cc(OC)c(NC(=O)C(C(=O)O)c2ccccc2)c(OC)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(C(=O)NN)C(C(=O)Nc1c(OC)cc(OC)cc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of α-[[(2,4,6-trimethoxyphenyl)amino]carbonyl]-benzene acetic acid (46.73 g, 0.1353 mol), and 1,1'-carbonyldiimidazole (24.7 g, 0.152 mol) in dry THF (1.0 L) was stirred at room temperature under nitrogen for 2 hours. A white solid precipitated. To the suspension was added tridecanoic acid hydrazide (30.90 g, 0.1353 mol), and the mixture was stirred at room temperature for 17 hours, then at 40° C. for 21 hours. The mixture was chilled (+5° C.) and filtered. The filtercake was washed (THF, ether, water) and dried under house vacuum/air stream; yield 54.36 g (72%); mp 175°-180° C.