Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH:4]12[CH2:9][CH:8]1[CH2:7][N:6]([C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[C:13]([C:27]([OH:29])=O)=[CH:12][N:11]=1)[CH2:5]2.[OH:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([NH2:37])[CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:4]12[CH2:9][CH:8]1[CH2:7][N:6]([C:10]1[N:15]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([F:26])[CH:19]=3)[C:13]([C:27]([NH:37][C@H:34]3[CH2:35][CH2:36][C@H:31]([OH:30])[CH2:32][CH2:33]3)=[O:29])=[CH:12][N:11]=1)[CH2:5]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1F
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)N[C@H]2CC[C@H](O)CC2)cc1F
Reaction time: 17 h

Procedure:
In the mixture of DCM (20 mL) and THF (20 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (580 mg, 1.62 mmol), trans-4-hydroxycyclohexylamine (187 mg, 1.62 mmol), TEA (485 mg, 4.79 mmol) and HATU (2-(7-azobenzotriazole)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (743 mg, 1.95 mmol). The reaction was conducted at ambient temperature for 17 h. The solvent was removed by evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and concentrated to give a solid, which was purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)-N-(trans-4-hydroxycyclohexyl)pyrimidine-5-formamide as a faint yellow solid (200 mg, 27.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH:15]([CH3:17])[CH3:16])[CH2:12][N:11]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([C:28]4([CH3:31])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:34]>>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33](=[O:34])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([C:28]4([CH3:31])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:12]2)[CH:15]([CH3:16])[CH3:17])=[CH:37][CH:38]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CC(C)N[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Product: CC(C)N(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step h), the title compound rac-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-isopropyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-isopropylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenyl chloroformate and was obtained as a colorless foam. MS m/e: 604.3 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([OH:20])=O)[CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[N:46][C:45]=1[C:50]1[CH:55]=[CH:54][C:53]([N:56]2[CH2:61][CH:60]3[CH2:62][CH:57]2[CH2:58][NH:59]3)=[CH:52][CH:51]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([CH:12]2[CH2:16][CH2:15][N:14]([CH2:17][C:18](=[O:20])[N:59]3[CH2:58][CH:57]4[CH2:62][CH:60]3[CH2:61][N:56]4[C:53]3[CH:54]=[CH:55][C:50]([C:45]4[N:44]=[CH:49][CH:48]=[CH:47][N:46]=4)=[CH:51][CH:52]=3)[CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)CN1CCC(C(=O)Nc2ccc(O)c(Cl)c2)C1
Reactant: c1cnc(-c2ccc(N3CC4CC3CN4)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(O)c(Cl)c1)C1CCN(CC(=O)N2CC3CC2CN3c2ccc(-c3ncccn3)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.8 %

Procedure:
To a mixture of [3-(3-Chloro-4-hydroxy-phenylcarbamoyl)-pyrrolidin-1-yl]-acetic acid (10 mg, 0.034 mmol) and HOBt (6.8 mg, 0.050 mmol) in DMF (0.5 ml) at 0° C. was added EDCl (9.6 mg, 0.050 mmol). The formed reaction mixture was stirred at 0° C. for 0.5 hour and then 2-(4-Pyrimidin-2-yl-phenyl)-2,5-diaza-bicyclo[2.2.1]heptane hydrochloride salt (12.6 mg, 0.05 mmol) was added. After stirred at RT for overnight, the reaction mixture was purified using a Prep-HPLC to give titled compound (3.4 mg, 19% yield). Mass Spec ES (533.1, M+H)
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[CH:34]12[CH2:43][CH:38]3[CH2:39][CH:40]([CH2:42][CH:36]([CH2:37]3)[C:35]1=O)[CH2:41]2>C1COCC1.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[O:8]([C:16]1[CH:17]=[C:18]([C:19](=[C:35]2[CH:36]3[CH2:42][CH:40]4[CH2:39][CH:38]([CH2:43][CH:34]2[CH2:41]4)[CH2:37]3)[O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC(C3)CC2C4)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 500 mL three-neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and nitrogen line was charged with 200 mL anhydrous THF. Fifteen parts of titanium tetrachloride was added dropwise over a period of 30 minutes. After stirring the suspension for 20 minutes, 22 parts of zinc was added in small portions. The reaction mixture was heated under reflux for 2 hours and 37 mL of triethylamine was added dropwise. After refluxing one hour a solution 5.9 parts of alkene (54) and 3.0 parts of adamantan-2-one in 40 mL of dry THF was added over a period of 90 minutes. The reaction mixture was heated for one hour. TLC on silica gel plate of the mixture showed the presence of starting ester. One and a half part of Adamantan-2-one in 20 mL of dry THF was added dropwise over 30 minutes and refluxed for two hours. The mixture was cooled to room temperature, diluted with 500 mL of hexane and decanated. The residue was washed three times with 200 mL of hexane. The combined hexane layer was filtered and evaporated under reduced pressure to give an oily material which was purified by chromatography on silica gel column using 2.5% ethyl acetate/hexane as an eluant. The fractions were checked by TLC on silica gel plate and the desired fractions were combined. The solvent was evaporated under reduced pressure to give an oil, yield 6.30 parts. The structure was confirmed by 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:3]1=2.O1C2C(=CC=C(O)C=2)CCC1.[O:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32](=[O:39])[C:31]1=[O:40].C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:39][C:32]1([C:10]2[C:9]([OH:12])=[CH:8][C:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]=3[CH:11]=2)[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:30]([CH2:29][C@H:25]2[CH2:26][CH2:27][CH2:28][O:24]2)[C:31]1=[O:40]
Reactant: O=C1C(=O)N(C[C@H]2CCCO2)c2ccccc21
Reactant: CN1CCOc2cc(O)ccc21
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: Oc1ccc2c(c1)OCCC2
Product: CN1CCOc2cc(O)c(C3(O)C(=O)N(C[C@H]4CCCO4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 13A, and making non-critical variations using 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replace chroman-7-ol, and 1-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-indole-2,3-dione to replace 1-(diphenylmethyl)indoline-2,3-dione, 3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-[(2R)-tetrahydrofuran-2-ylmethyl]-1,3-dihydro-2H-indol-2-one was obtained (91%) as a pale grey solid: 1H NMR (300 MHz, CDCl3) (diastereomers) δ8.94 (s, 0.4H), 8.80 (s, 0.6H), 7.52-7.48 (m, 1H), 7.41-7.34 (m, 1H), 7.20-7.08 (m, 2H), 6.52 (s, 1H), 6.16 (s, 1H), 4.51 (s, 0.4H), 4.44 (s, 0.6H), 4.29-4.17 (m, 3H), 3.90-3.64 (m, 4H), 3.17-2.99 (m, 2H), 2.58 (s, 3H), 2.04-1.78 (m, 3H), 1.74-1.60 (m, 1H); 13C NMR (diastereomers) (75 MHz, CDCl3) δ179.4, 179.2, 149.4, 149.3, 146.2, 143.2, 143.0, 130.2, 130.1, 129.8, 129.6, 125.9, 125.7, 123.6, 123.5, 117.6, 112.7, 112.4, 110.4, 110.3, 107.4, 79.3, 79.2, 76.9, 76.7, 68.3, 68.2, 65.3, 49.5, 44.7, 44.6, 39.5, 29.3, 29.1, 25.7, 25.6; MS (ES+) m/z 419.1 (M+23).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1>CN(C=O)C>[ClH:2].[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:39][CH2:40][CH2:41][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:9])=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]2[S:21][CH:22]=[C:23]([CH3:25])[N:24]=2)[CH:14]=1
Reactant: NCCN1CCCC1
Reactant: Cc1csc(Nc2cc(Oc3cc(C(=O)O)ccc3Cl)ccn2)n1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cc(C(=O)NCCN4CCCC4)ccc3Cl)ccn2)n1
Yield: 33.8 %

Procedure:
Following procedure of Example 83, 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)benzoic acid hydrochloride (0.1 g, 0.2511 mmol), triethylamine (0.1016 g, 1.004 mmol), DMF (3 mL), added ethyl carbonochloridate (0.02641 mL, 0.2762 mmol), N-(2-aminoethyl)pyrrolidine (0.05734 g, 0.5022 mmol) were reacted to afford 4-chloro-3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide hydrochloride (0.021 g, 15.22% yield) as off white solid. 1H NMR (DMSO) δ 11.26 (bs, 1H), 10.18 (bs, 1H), 8.98 (t, 1H), 8.23 (d, 1H), 7.92 (dd, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 6.58 (m, 3H), 3.61 (m, 4H), 3.31 (q, 2H), 3.02 (m, 2H), 2.21 (d, 3H), 2.00 (m, 2H), 1.86 (m, 2H); Mass spectrum (esi) m/z 458 (100) (M+H—HCl).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.NCCC(NC1SC(C2C=CN=C(NC3C=CC(Cl)=CC=3)N=2)=C(C)N=1)=O.ClCCN1CCOCC1>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:35][CH2:34][CH2:33][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Reactant: NCCN1CCOCC1
Agent: Cc1nc(NC(=O)CCN)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Agent: ClCCN1CCOCC1
Solvent: CC#N
Product: Cc1nc(NC(=O)CCNCCN2CCOCC2)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 2-morpholin-4-yl-ethylamine (or 3-amino-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 4-(2-chloro-ethyl)-morpholine. Anal. RP-HPLC: tR=11.5 min (10-70% MeCN, purity>97%). 1H-NMR (DMSO-D6) δ 1.52 (d, 2H, J=7.0 Hz, CH2), 2.48 (m, 2H, CH2), 2.52 (s, 3H, CH3), 3.05-3.11 (m, 4H, CH2), 3.25-3.28 (m, 6H, CH2), 4.08 (m, 2H, CH2), 7.13 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.29 (m, 2H, Ph-H), 7.82 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.82 (brs, 1H, NH).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:12]([CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[CH:13]([OH:15])[CH3:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:1][S:2]([O:15][CH:13]([CH:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:16][CH2:17][O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:20]([CH3:21])[CH3:22])[CH:23]([CH3:25])[CH3:24])[CH3:14])(=[O:4])=[O:3]
Reactant: CC(O)C(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(CCO[Si](C(C)C)(C(C)C)C(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
0.46 mL of methanesulfonyl chloride was added dropwise to a solution of 1.0 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-ol and 1.67 mL of triethylamine in 10 mL of an ethyl acetate at a temperature of 5° C. to 10° C., and the obtained mixture was then stirred at room temperature for 5.5 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and it was washed with a saturated sodium chloride aqueous solution and was then dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure, so as to obtain 1.2 g of 3-phenyl-5-((tris(propan-2-yl)silyl)oxy)pentan-2-yl methanesulfonate in the form of a yellow oily product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([Mg]Cl)(C)C.[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25](=[O:32])[C:24]2=[O:33])=[CH:20][CH:19]=1.Cl>O1CCCC1.ClCCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:25]2([OH:32])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:23]([CH2:22][C:21]3[CH:34]=[CH:35][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[C:24]2=[O:33])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1O
Reactant: COc1ccc(CN2C(=O)C(=O)c3ccccc32)cc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCCl
Product: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
To a stirred solution of 2,4-dihydroxybenzonitrile (4.33 g, 32.1 mmol) in tetrahydrofuran (50 mL) and 1,2-dichloroethane (400 mL) was added isopropylmagnesium chloride (17.7 mL, 2.0 M solution in tetrahydrofuran, 35.4 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and at ambient temperature for 2 h, and 1-(4-methoxybenzyl)-1H-indole-2,3-dione (8.58 g, 32.1 mmol) was added to the reaction mixture. The mixture was stirred at reflux for 18 h, cooled to 0° C. and 5% v/v hydrochloric acid was added. The organic layer was separated and washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate/hexanes (1/1) to afford 2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.30 g, 79%): 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.35 (s, 1H), 7.80 (s, 1H), 7.32 (d, J=9.0 Hz, 1H), 7.14-7.08 (m, 1H), 6.88-6.84 (m, 4H), 6.75-6.72 (m, 1H), 6.63 (s, 1H), 6.30 (s, 1H), 4.79 (ABq, 2H), 3.70 (s, 3H); MS (ES+) m/z 384.8 (M−17).
Reaction SMILES: [CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][O:22][CH3:23])[C:10]([CH:19]=O)=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2].[CH2:24]([O:26][C:27](=[O:48])[CH:28]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:25]>C1COCC1>[CH2:1]([C:3]1[N:7]2[N:8]=[C:9]([CH2:21][O:22][CH3:23])[C:10](/[CH:19]=[CH:28]/[C:27]([O:26][CH2:24][CH3:25])=[O:48])=[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)[C:6]2=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1ccc2c(-c3cncc(C)c3)c(C=O)c(COC)nn12
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(COC)nn2c(CC)ccc2c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazine-3-carbaldehyde (48 mg) and ethyl(triphenylphosphoranylidene)acetate (56.8 mg) in THF (3 mL) was stirred at ambient temperature for 2 hours. After evaporation of solvent, the residue was purified by silica gel column chromatography eluting with a mixture of hexane and AcOEt (5:1-2:1) to give ethyl(2E)-3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]acrylate as a yellow powder (30 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>CC(O)=O>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol) in 2 ml of HOAc was added Br2 (0-5 ml, 9.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexane 1/20) to yield the desired product (2.54 g) as a white solid. 1H NMR δ 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[CH3:31][NH:32][CH3:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:32]([CH3:33])[CH3:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN(C)C)c1Cl

Procedure:
In a manner similar to Paragraph E above, N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) in DMF (5 mL) was reacted with dimethylamine (1.33 M in tetrahydrofuran, 7.5 mL, 10 mmol) to give N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; which was purified by lyophilization from aqueous HCl to afford N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; hydrochloric acid salt, as a white solid; NMR (DMSO-d6/TFA) 10.9 (s, 1), 10.1 (br s, 1), 9.5 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1). 7.8 (dd, 1), 7.3 (dd, 2), 4.3 (br s, 2), 3.9 (s, 3), 2.8 (br s, 6) ppm.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[CH:20][C:21](Cl)=[O:22].Cl>O1CCCC1.C(O)C>[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH:19]=[CH:20][C:21]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:22]
Reactant: C1CNCCN1
Reactant: O=C(Cl)C=Cc1ccco1
Agent: Br
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=Cc1ccco1)N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a homogeneous solution of 15.6 g. (80 mM) of piperazine hexahydrate and 13.8 g. (80 mM) of 47% hydrobromic acid in 40 ml. of ethanol there were added dropwise at room temperature another solution of 6.3 g. (40 mM) of 3-(Furan-2-yl)-acryloylchloride in 10 ml. of tetrahydrofuran. After stirring for two hours at room temperature, the resulting solution was heated at 80° for two hours. Then the solution was cooled with ice and the forming crystals of piperazine hydrobromide were filtered off. The filtrate was condensed under reduced pressure and 80 ml. of 2 N-hydrochloric acid was added into the residue. After neutral substances were removed by extraction with ethyl acetate, the resulting solution was made alkaline with 5 N sodium hydroxide and extracted again with ethyl acetate. After drying over anhydrous sulfate, the combined extracts were condensed to give 4.62 g. of 3-(Furan-2-yl)-acryloylpiperazine (56% yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH2:13][S:14][CH3:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:19](O)[CH:20]([CH3:22])[CH3:21].C(Cl)CCl>O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:19]([O:17][C:16](=[O:18])[C@H:11]([CH2:12][CH2:13][S:14][CH3:15])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CO
Reactant: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: ClCCCl
Product: CSCC[C@H](NC(=O)Cc1ccccc1)C(=O)OCC(C)C
Temperature: 23 °C
Reaction time: 17 h

Procedure:
N-phenylacetyl-L-methionine (0.1285 g, 0.447 mmol) was dissolved in 3.0 mL dioxane and iso-butyl alcohol (0.2 mL) and treated with EDC (0.094 g, 0.492 mmol), and catalytic DMAP (0.015 g). After stirring for 17 hours at 23° C., the mixture was evaporated at reduced pressure to an oil, the residue was diluted in EtOAc and washed with 0.1 N HCl and saturated sodium bicarbonate. Chromatography on silica gel using 98:2 CHCl3/MeOH as eluant provided the pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])[C:11]([CH3:24])=[C:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.CO.O.[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11]([CH3:24])=[C:10]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[S:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:33])=[O:34])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2ccnc(Cl)c2)n1CC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)cc(-c2ccnc(Cl)c2)n1CC(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of crude benzyl 2-(5-(2-chloropyridin-4-yl)-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (514 mg, 0.360 mmol, contaminated with ˜60% 2-(phenylsulfonyl)phenyl)methanol) in tetrahydrofuran (4 mL) and water (4 mL) was added a 3M solution of aqueous sodium hydroxide (28.8 mg, 0.720 mmol). The reaction turned yellow upon addition of the base solution, and the reaction was stirred at room temperature for 20 minutes after which LCMS analysis indicated that the saponification was complete. The reaction was concentrated to remove the THF, and then diluted in water and washed with dichloromethane (2×50 mL) and ethyl acetate (1×50 mL). The water layer was acidified to pH=4 with 3M aqueous hydrochloric acid solution. The product was extracted with ethyl acetate and washed with a brined aqueous layer (3×50 mL), dried (sodium sulfate), filtered and concentrated to a yellow solid. A significant loss of product was observed. In order to recover additional product, the aqueous layer prior to the final extraction was further acidified and re-extracted with ethyl acetate (3×50 mL), dried (sodium sulfate), filtered and concentrated. The batches were combined to afford 2-(5-(2-chloropyridin-4-yl)-2-methyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid as a yellow solid (99.5 mg, 0.207 mmol, 58% yield). 1H NMR (400 MHz, CDCl3): δ (ppm) 8.31 (d, 1H), 8.27 (d, 1H), 7.85 (m, 2H), 7.40-7.56 (m, 5H), 7.13-7.16 (m, 2H), 7.04 (d, 1H), 5.85 (s, 1H), 4.64 (s, 2H), 4.05 (s, 2H), 2.00 (s, 3H).