Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][C:3]=1[C:18]([NH:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=1)=[O:19].[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[CH:4][C:3]=1[C:18]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1)=[O:19]
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(OC)c3)ccc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(COc2ccc(Cl)c(C(=O)NCc3ccc(C(=O)O)cc3)c2)c1

Procedure:
A solution of methyl 4-[({[2-chloro-5-({[3-(methyloxy)phenyl]methyl}oxy)phenyl]carbonyl}amino)methyl]benzoate (106 mg, 0.24 mmol) and lithium hydroxide (2 eq, 20 mg, 0.48 mmol) in dioxane (3 ml) and H2O (1.5 ml) was heated at 65° C. for 3 hours. On cooling solvent was evaporated in vacuo, residue acidified with 2M HCl and filtered to give the title compound as a white solid. MS (ES+) m/z 426 [M+H]+ (C23H2035ClNO5). 1H-NMR (400 MHz, d6-DMSO) δ 3.76 (3H, s), 4.50 (2H, d, J 6), 5.12 (2H, s), 6.91 1H, dd, J 1.6, J 7.6), 7.02 (1H, s), 7.09 (2H, m), 7.30 (1H, t, J 4), 7.40-7.47 (2H, m), 7.92 (2H, d, J 8), 9.04 (1H, t, J 6)
Reaction SMILES: I[C:2]1[C:6]2[C:7]([O:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][CH:9]=[CH:10][C:5]=2[N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.N1C=C([C:42]2[C:46]3C(OC4CCOCC4)=NC=C[C:45]=3[N:44]([C:58]([C:71]3[CH:76]=[CH:75]C=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:43]=2)C=N1.BrCC1CC1>>[CH:71]1([CH2:58][N:44]2[CH:45]=[C:46]([C:2]3[C:6]4[C:7]([O:11][CH:12]5[CH2:13][CH2:14][O:15][CH2:16][CH2:17]5)=[N:8][CH:9]=[CH:10][C:5]=4[NH:4][N:3]=3)[CH:42]=[N:43]2)[CH2:76][CH2:75]1
Reactant: c1ccc(C(c2ccccc2)(c2ccccc2)n2nc(-c3cn[nH]c3)c3c(OC4CCOCC4)nccc32)cc1
Reactant: Ic1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccnc(OC3CCOCC3)c12
Agent: BrCC1CC1
Product: c1cc2[nH]nc(-c3cnn(CC4CC4)c3)c2c(OC2CCOCC2)n1
Yield: 71 %

Procedure:
Prepared by a procedure analogous to Example 86 using 3-iodo-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine as starting material and by reacting 3-(1H-pyrazol-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with (bromomethyl)cyclopropane to give the title compound (45.5 mg, 71% over two steps). LC-MS (Method G): m/z=340.1 [M+H]+; 3.63 min. 1H-NMR (400 MHz, DMSO): δ 13.27 (s, 1H), 8.28 (s, 1H), 8.01 (s, 1H), 7.83 (d, J=5.9, 1H), 7.07 (d, J=6.0, 1H), 5.53-5.43 (m, 1H), 4.06 (d, J=7.0, 2H), 3.95-3.85 (m, 2H), 3.53 (t, J=10.3, 2H), 2.20-2.10 (m, 2H), 1.86-1.72 (m, 2H), 1.35-1.24 (m, 1H), 0.62-0.53 (m, 2H), 0.45-0.38 (m, 2H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])=[CH:6][CH:5]=1)N.[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][CH2:28][CH2:29][CH:30]=O.C(OCC)(=O)C>C(O)(=O)C>[O:16]=[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19](=[O:26])[N:18]1[CH2:27][CH2:28][C:29]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH:8]=2)[NH:2][CH:30]=1
Reactant: CN(C)C(=O)Cc1ccc(NN)cc1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A mixture of 2-(4-hydrazinophenyl)-N,N-dimethylacetamide hydrochloride (0.875 g, contains 0.00315 mol) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal, diethyl acetal (0.873 g) was heated under reflux in 25% aqueous acetic acid (100 ml) for 30 min. The mixture was poured into ethyl acetate (150 ml) and the aqueous phase was separated. This was washed with ethyl acetate (150 ml) and the organic extracts were combined. The yellow solution was washed successively with water (150 ml) 8% sodium bicarbonate solution (150 ml) and finally water (150 ml). Evaporation of the dried (Na2SO4) solvent gave a yellow solid which crystallised from propan-2-ol to give the title compound as a pale yellow powder (0.91 g) m.p. 193°-4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][O:8][C@@H:9]2[C@@H:17]([CH:18]=[CH2:19])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[S:14]3)[C@H:10]2[O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:5][CH:4]=1>[Ni].C(O)C>[CH2:18]([C@H:17]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])[S:14]2)[CH:10]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C@@H:9]1[O:8][CH2:7][C:6]1[CH:39]=[CH:40][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:19]
Reactant: C=C[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Agent: [Ni]
Solvent: CCO
Product: CC[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2C(OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Yield: 90.6 %

Procedure:
A solution of above crude compound 45 (220 mg, purity 50%) was dissolved into ethanol (15 mL) and treated with Ranney Ni (100 mg) under H2 atmosphere overnight at room temperature. After filtration, the organic solution was concentrated to give crude compound 46 (200 mg, purity 48% by LC-MS), which was used in the next step without further purification. (ES, m/z): [M+H]+ 573.0.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CCN(C(C)C)C(C)C.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:27][C:26]=1[S:35]([N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1)(=[O:37])=[O:36]
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cc(C(F)(F)F)ccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2cc(C(F)(F)F)ccc2Br)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 103 %

Procedure:
To a solution of 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (1.18 g, 4.98 mmol) in dichloromethane (40 ml) was added DIPEA (2.70 ml, 15.45 mmol) and then 2-bromo-5-(trifluoromethyl)benzenesulfonyl chloride (1.613 g, 4.98 mmol). The reaction mixture was stirred for 1 h 20 min at room temperature. The reaction mixture was then washed with water (50 ml), dried on a phase separation cartridge and concentrated under vacuum to give the crude title compound (2.5 g) which was used directly in the next step.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].N(C(OC(C)(C)C)=O)[C@H](C(NCC(O)=O)=O)C.Cl.[S:39]1[C:43]2C=CC=C[C:42]=2[N:41]=[C:40]1[CH:48]([OH:54])[C@@H:49]1[CH2:53][CH2:52][CH2:51][NH:50]1.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[S:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:48]([OH:54])[C@@H:49]1[CH2:53][CH2:52][CH2:51][N:50]1[C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4](=[O:5])[C@H:2]([CH3:3])[NH:1][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: OC(c1nc2ccccc2s1)[C@@H]1CCCN1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(O)c1nccs1
Reaction time: 8 h

Procedure:
1 eq of Boc-Ala-Val-OH or Boc-Ala-Gly-OH and 0.9 eq of 36 or 37, 1.1 eq of HOBt, and 1.1 eq of WSCD were dissolved in dry ACN. After addition of 0.9 eq of TEA the mixture was stirred overnight. The solvent was removed and the remaining oil was dissolved in ethyl acetate. The solution was washed with brine and dried.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.[F:17][C:18]1[CH:19]=[C:20]([NH2:26])[CH:21]=[N:22][C:23]=1[O:24][CH3:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:16][C:5]1[CH:6]=[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[C:2]([NH:26][C:20]2[CH:21]=[N:22][C:23]([O:24][CH3:25])=[C:18]([F:17])[CH:19]=2)=[N:3][CH:4]=1
Reactant: COc1ncc(N)cc1F
Reactant: Cc1nc(N)nc(-c2cc(F)cnc2Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(F)cc2-c2nc(C)nc(N)n2)cc1F
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
A solution of 4-(2-chloro-5-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (100 mg, 0.417 mmol) and 5-fluoro-6-methoxypyridin-3-amine (120 mg, 0.844 mmol) (Anichem, N.J., USA) in THF (2.0 mL) was cooled in an ice bath under nitrogen. A THF solution of LiHMDS (1 M in THF, 2500 μL, 2.500 mmol) was added dropwise. After 5 min, the cooling bath was removed. After a total of 22 min, HCl (5N, 0.5 mL) was added. After 5 min, EtOAc (10 mL) and saturated NH4Cl (10 mL) were added. The organic layer was washed with water (2×5 mL). The combined aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was suspended in MeOH (5 mL) and filtered. The solid was washed with MeOH (2×2 mL), DCM (3×3 mL) and EtOAc (3×3 mL) to give the first batch of product as a brown solid. The combined washings were concentrated and purified on silica using 0-3% MeOH in DCM. The dark blue fraction contained the desired product (m/z 346) as a second batch. The combined product batches was suspended in ether (4 mL) and filtered to give the final product as a green solid (60 mg). LCMS (ES, pos.): calcd for C15H13F2N7O: 345.1. found: 346.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (s, 1H); 8.56 (dd, J=9.78, 2.93 Hz, 1H); 8.38 (br. s., 2H); 8.28 (dd, J=12.81, 1.86 Hz, 1H); 7.97 (br. s., 1H); 7.84 (br. s., 1H); 3.93 (s, 3H); 2.44 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −140.84 (s, 1F); −139.70 (s, 1F).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[C:9](Cl)([Cl:11])=[O:10]>C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[N:3]1[C:9]([Cl:11])=[O:10]
Reactant: O=C(Cl)Cl
Reactant: CC1CCCC(C)N1
Solvent: c1ccccc1
Product: CC1CCCC(C)N1C(=O)Cl

Procedure:
To a solution of 50 g of 2,6-dimethylpiperidine in 300 ml of benzene is added 60 g of phosgene and the mixture is refluxed for 3 hours. The solid which had separated was filtered and the filtrate was concentrated and distilled under vacuum to obtain 2,6-dimethylpiperidinoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: COc1ccc(-c2ccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)nc2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)[O-])CCO5)cc3)nc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6′-methoxy-3,3′-bipyridin-6-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.040 g, 0.0752 mmol) in 1:1 THF/MeOH (2 ml) was added a 0.5M solution of sodium methoxide in methanol (0.150 ml, 0.0752 mmol), and the reaction was stirred for 2 hours at ambient temperature. The reaction was concentrated to yield the desired compound (0.040 g, 0.0722 mmol, 96.0% yield). MS (apci) m/z=532.2 (M-Na+2H).
Reaction SMILES: Br.Br.[CH2:3]([N:10]1[C@@H:15]2[CH2:16][C@@H:12]([NH:13][CH2:14]2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=2)[N:23]=1>>[CH2:3]([N:10]1[CH2:11][CH:12]2[CH2:16][CH:15]1[CH2:14][N:13]2[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]([F:28])([F:30])[F:29])=[N:25][N:26]=2)[N:23]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(CN2C[C@H]3C[C@@H]2CN3)cc1
Agent: Br
Product: FC(F)(F)c1nnc2ccc(N3CC4CC3CN4Cc3ccccc3)nn12

Procedure:
A mixture of (1R,4R)-6-benzyl-3,6-diazabicyclo[2.2.1]heptane dihydrobromide and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 4. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.2% aqueous ammonia) and acetonitrile as eluents to give 6-(5-benzyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([OH:13])[CH2:9][CH2:10][CH2:11][OH:12].[OH-].[Na+].C(Cl)C1C=CC=CC=1>O>[CH2:7]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:13])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCO
Reactant: Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCc1ccccc1
Product: OCCCCOCc1ccccc1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
A mixture of toluene (50 ml), 1,4-butanediol (212 g, 2.35 mol) and sodium hydroxide (47.7 g) was heated up to 95° C., and thermally insulated at the same temperature for 30 minutes. Thereafter, benzyl chloride (150 g, 1.185 mol) was added and the mixture was thermally insulated at 95 to 105° C. for 4 hours, then, poured into water (250 ml). After neutralization with 35% hydrochloric acid, the organic layer was liquid-partitioned and the aqueous layer was extracted with toluene (100 ml). The organic layers were combined and washed with saline (100 ml). The organic layer was concentrated under reduced pressure, and the residue was distilled under reduced pressure, to obtain a title compound (115 g, yield 53.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:5]([Cl:18])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:18][C:5]1[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:7][C:2]([NH:19][C:20]2[CH:21]=[C:22]([CH2:26][CH2:27][CH2:28][OH:29])[CH:23]=[CH:24][CH:25]=2)=[N:3][CH:4]=1
Reactant: COc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: Nc1cccc(CCCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cccc(CNc2nc(Nc3cccc(CCCO)c3)ncc2Cl)c1
Temperature: 105 °C
Yield: 64.5 %

Procedure:
Into a reaction flask were added 2,5-dichloro-N-(3-methoxybenzyl)pyrimidin-4-amine (0.20 g, 0.70 mmol, prepared according to Example 1, step A), 1,4-dioxane (20 mL), 3-(3-aminophenyl)propan-1-ol (0.16 g, 1.0 mmol, prepared according to Example 12, step A & B), and p-toluenesulfonic acid monohydrate (0.049 g, 0.26 mmol). The mixture was heated at 105° C. for 2 days and NaHCO3 (saturated aqueous solution) was added. The organic solvent was removed under vacuum followed by an addition of water and EtOAc. The aqueous layer was extracted with EtOAc twice. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product (0.18 g, 64%) as a white solid. LCMS for C21H24lN4O2 (M+H)+: m/z=399.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:17]([CH3:16])(=[O:19])=[O:18])[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: Cn1c(C#N)ccc1-c1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using methane sulfonyl chloride (43 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-N-(methylsulfonyl)methanesulfonamide (0.021 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1I)[CH:14]=[CH:13][S:12]2.C([Mg]Cl)(C)C.I[C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([CH:33]([CH3:35])[CH3:34])=[N:31][N:32]=2)[N:29]=1.CN(C=O)C>C1COCC1.O.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[O-]S([O-])(=O)=O.[Zn+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:24]1[CH:25]=[CH:26][C:27]3[N:28]([C:30]([CH:33]([CH3:35])[CH3:34])=[N:31][N:32]=3)[N:29]=1)[CH:14]=[CH:13][S:12]2
Reactant: Fc1ccc(-c2nc3sccn3c2I)c(F)c1
Reactant: CC(C)c1nnc2ccc(I)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4sccn34)nn12
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 22.8 %

Procedure:
The 6-(2,4-difluorophenyl)-5-iodoimidazo[2,1-b]thiazole (1.00 g, 2.76 mmol) was suspended in THF (7.5 mL) then cooled to about −30° C. The i-PrMgCl (2 M in THF, 1.52 mL, 3.04 mmol) was added dropwise over about 15 min then stirred at about −30° C. for about 15 min. The ZnCl2 (0.489 g, 3.59 mmol) was dissolved in THF (7.5 mL), cooled to about 0° C., and added dropwise to the Grignard solution. The reaction mixture was stirred for about 30 min at about −30° C. The 6-iodo-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.796 g, 2.76 mmol) was added to DMF (7.50 mL) and heated to about 80° C. to dissolve the material. Pd(Ph3P)4 (0.128 g, 0.110 mmol) was then added to the solution and the mixture was immediately added to the zincate suspension. The mixture was immediately heated to about 55° C. for about 45 min, then cooled, diluted with water and extracted with EtOAc. The organic solution was dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel with DCM/MeOH (95:5) followed by trituration with MeOH (5 mL) gave a solid that was collected by filtration. The filtrate was concentrated under reduced pressure then purified by RP-HPLC using (Table 1, Method d). The desired fractions were concentrated under reduced pressure to give a solid that was collected by filtration. The two crops were combined to give the title compound (0.250 g, 23%): LC/MS (Table 1, Method a) Rt=2.46 min; MS m/z: 397.2 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[Cl:14].ClC1C=C([N+]([O-])=O)C(OC)=CC=1C.ClC1C=C([N+]([O-])=O)C(OC)=CC=1C(Br)Br.[CH2:43]([O:45][P:46]([O:50]CC)[O:47][CH2:48][CH3:49])[CH3:44]>C1(C)C=CC=CC=1>[CH2:43]([O:45][P:46]([CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1[Cl:14])(=[O:50])[O:47][CH2:48][CH3:49])[CH3:44]
Reactant: CCOP(OCC)OCC
Reactant: COc1cc(CBr)c(Cl)cc1[N+](=O)[O-]
Agent: COc1cc(C(Br)Br)c(Cl)cc1[N+](=O)[O-]
Agent: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1cc(OC)c([N+](=O)[O-])cc1Cl)OCC

Procedure:
A mixture of 1-Bromomethyl-2-chloro-5-methoxy-4-nitro-benzene, 1-Chloro-4-methoxy-2-methyl-5-nitro-benzene and 1-chloro-2-dibromomethyl-4-methoxy-5-nitro-benzene (Compound 56G, 24 g, 1:015:0.5) in toluene (100 mL) were treated with triethylphosphite (15.6 g, 94.2 mmol) and heated to reflux for 24 hrs. Toluene and triethylphosphite were distilled off under reduced pressure. The residue was treated with hot diisopropyl ether to give 10 g of the required compound as dark yellow crystals.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].[CH3:5][C:6]([CH3:30])([CH3:29])[CH2:7][C:8]1[N:9]=[C:10]([CH:13]([NH2:28])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[NH:11][CH:12]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:5][C:6]([CH3:30])([CH3:29])[CH2:7][C:8]1[N:9]=[C:10]([CH:13]([NH:28][C:1](=[O:4])[CH3:2])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[NH:11][CH:12]=1
Reactant: CC(=O)O
Reactant: CC(C)(C)Cc1c[nH]c(C(N)Cc2ccc(-c3ccc(F)cn3)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CC(=O)NC(Cc1ccc(-c2ccc(F)cn2)cc1)c1nc(CC(C)(C)C)c[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic acid (24 μL, 0.43 mmol) was added to an ambient temperature solution of 1-[4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (for synthesis see Example 8) (76 mg, 0.22 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol), 1-hydroxybenzotriazole (59 mg, 0.43 mmol) and sodium bicarbonate (183 mg, 2.2 mmol) in methylene chloride (3 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with brine and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparative plate chromatography eluting with 5% methanol/ethyl acetate afforded the title compound. High pressure liquid chromatography (Chiralcel AD column) eluting with 10% ethanol/hexane afforded the two pure enantiomers. 1H NMR (500 MHz, CD3OD) δ 8.48 (s, 1H), 7.87-7.80 (m, 3H), 7.68-7.62 (m, 2H), 7.24 (d, J=10 Hz, 2H), 6.66 (s, 1H), 5.22 (t, J=10 Hz, 1H), 3.35 (s, 3H), 3.29 (m, 1H), 3.18 (m, 1H), 2.40 (s, 2H) 0.86 (s, 9H); (M+H) found: 395.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(N[S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])C=CC=2)C=CN=1.[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[N:43][C:42]=2[C:52]2[C:53]([O:59][CH3:60])=[C:54]([CH:56]=[CH:57][CH:58]=2)[NH2:55])[CH:38]=[CH:37][N:36]=1.FC1C=CC=C(F)C=1S(Cl)(=O)=O>>[Cl:34][C:35]1[N:40]=[C:39]([C:41]2[S:45][C:44]([N:46]3[CH2:47][CH2:48][O:49][CH2:50][CH2:51]3)=[N:43][C:42]=2[C:52]2[C:53]([O:59][CH3:60])=[C:54]([NH:55][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:56]=[CH:57][CH:58]=2)[CH:38]=[CH:37][N:36]=1
Reactant: COc1c(N)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Agent: O=S(=O)(Cl)c1c(F)cccc1F
Product: COc1c(NS(=O)(=O)c2c(F)cccc2F)cccc1-c1nc(N2CCOCC2)sc1-c1ccnc(Cl)n1
Yield: 27.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-(5-(2-chloropyrimidin-4-yl)-2-morpholinothiazol-4-yl)-2-methoxyaniline (26.1 g, 64.7 mmol) and 2,6-difluorobenzene-1-sulfonyl chloride (13.8 g, 64.7 mmol) the title compound of Step C was obtained (10.2 g, 27.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 (d, J=5.5 Hz, 1H), 7.62-7.71 (m, 1H), 7.38-7.45 (m, 1H), 7.15-7.30 (m, 4H), 6.40 (d, J=5.5 Hz, 1H), 3.67-3.78 (m, 4H), 3.50-3.61 (m, 4H), 3.18 (s, 3H). MS (ES+): 580 [M+H]+.