Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[C:9]3[N:10]([CH3:18])[C:11]4[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][C:16]=4[C:8]=3[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.N12CCCN=C1CCCCC2.[CH3:30][N:31]=[C:32]=[O:33].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[CH3:30][NH:31][C:32](=[O:33])[O:17][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:18])[C:9]3[CH:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)[CH2:6][CH2:7][C:8]=3[C:16]=2[CH:15]=1
Reactant: Cn1c2c(c3cc(O)ccc31)CCC2NC1CC1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCC2=NCCCN2CC1
Product: CNC(=O)Oc1ccc2c(c1)c1c(n2C)C(NC2CC2)CC1
Temperature: 0 °C

Procedure:
3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol7-ol (2.2 g) was dissolved in CH2Cl2 (200 ml) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU; 0.21 g) and the solution was cooled to 0° C. A solution of methyl isocyanate (0.52 g in 30 ml CH2Cl2) was added slowly to the cooled solution and the reaction was monitored by thin layer chromatography (silica gel, 1:1 hexane/ethyl acetate). After warming to room temperature, the mixture was washed successively with water (2+100 ml), brine (1×100 ml) and again with water (1×100 ml). The organic layer was dried over Na2SO4 and the solvent removed in vacuo. The crude material was recrystallized from acetonitrile. 3-(N-Cyclopropyl)amino-4-methyl-1,2,3,4-tetrahydrocyclopent[b]indol7-yl methylcarbamate was isolated as light yellow/white plates (1.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]=O)[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16].C(#N)C.[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>ClCCl.C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:12][NH:24][CH:21]3[CH2:23][CH2:22]3)[CH:11]=1)[O:8][C:7]([CH3:15])([CH3:14])[CH2:6][C:5]2([CH3:17])[CH3:16]
Reactant: NC1CC1
Reactant: CC1(C)CC(C)(C)c2cc(Br)cc(C=O)c2O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: CC1(C)CC(C)(C)c2cc(Br)cc(CNC3CC3)c2O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A stirred, cooled (ice bath) solution of 6-bromo-2,2,4,4-tetramethyl chroman-8-carbaldehyde (U.S. Pat. No. 6,252,090, 2.4 g, 8.4 mmol) in dichloromethane (10 mL) and acetonitrile (9 mL) was treated with cyclopropyl amine (1.45 mL, 21 mmol). After 5 minutes, acetic acid (1 mL) was added followed by sodium cyanoborohydride (1.33 g, 21 mmol). The reaction mixture was stirred at ambient temperature for 2 h. The volatiles were distilled off in vacuo, the residue was diluted with water and extracted with ethyl acetate (×2). The combined organic extract was washed with water, saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to an oil. Flash column chromatography over silica gel (230-400 mesh) afforded the title compound (1.4 g, 50%) as a clear oil.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH3:8][C@@H:9]([NH2:18])[C@@H:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[CH3:8][CH:9]([NH:18][C:4](=[O:5])/[CH:3]=[CH:2]\[C:1]([OH:6])=[O:7])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:17]
Reactant: C[C@@H](N)[C@@H](O)c1ccccc1
Reactant: O=C1C=CC(=O)O1
Solvent: Cc1ccccc1
Product: CC(NC(=O)/C=C\C(=O)O)C(O)c1ccccc1
Temperature: 50 °C

Procedure:
32.6 grams of maleic anhydride were dissolved in 600 ml of toluene and there were dropped into this solution under stirring a 50° C. warm solution of 50.0 grams of (+)-norephedrine in 100 ml of toluene. Then stirring was continued for 30 more minutes at this temperature. The product was allowed to cool, filtered off with suction, dried and recrystallized from ethyl acetate. Yield: 63.5 grams=77.0% of theory. M.P. 154°-156°
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([CH3:8])=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][NH2:18])[CH:11]=1>>[CH3:9][C:4]1[CH:3]=[C:2]([NH:18][CH2:17][CH2:16][C:12]2[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: NCCc1cccnc1
Reactant: Cc1ccc(I)cc1C
Product: Cc1ccc(NCCc2cccnc2)cc1C

Procedure:
In analogy to the procedure described for the synthesis of example 22, step 1, the title compound was prepared from 4-iodo-o-xylene and 2-pyridin-3-yl-ethylamine (CAS: 20173-24-4). MS (m/e): 227.2 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N+:13]([O-])([OH:15])=[O:14]>OS(O)(=O)=O.O>[N+:13]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C@@H:2]([C:10]([OH:12])=[O:11])[NH2:1])=[CH:5][CH:6]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 50 %

Procedure:
10.0 g (60.6 mmoles) of L-phenylalanine was dissolved in 16 ml concentrated H2SO4 (95-98%, D. 1.84 g/ml) at 0° C. 3.0 ml of HNO3 (90%, D. 1.5 g/ml) was added dropwise to the stirring solution keeping temperature at about 0° C. After all of the HNO3 has been added, the solution was allowed to stir 10-15 minutes. Reaction solution was then poured over about 200 ml of ice and then diluted to about 700 ml with additional H2O. This solution was then heated to a boil, and neutralized with PbCO3, about 80 g. The resulting precipitate was filtered and the supernatant was treated with H2S(g) to precipitate remaining Pb++, and then filtered. The resulting filtrate was reduced to 1/3 its volume. The solid which formed was filtered and washed with 95% ethanol. Yield was 50-55% of p-nitrophenylalanine when recrystallized from boiling H2O.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[OH:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([OH:21])[C:19]=1[I:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13].I[CH2:23][CH3:24]>O>[CH2:23]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[C:18]([OH:21])[C:19]=1[I:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:24]
Reactant: CCI
Reactant: CCOC(=O)c1cc(O)c(I)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c(I)c(OCC)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% oil, 3.99 g) was added to a DMF (100 mL) solution of ethyl 3,5-dihydroxy-4-iodobenzoate (15.0 g), and the mixture was stirred at 0° C. for 30 minutes in a nitrogen atmosphere. Iodoethane (4.09 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.59 g).
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:10]1[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1>C(O)(=O)C>[CH2:15]1[C:10]2[NH:7][C:1]3[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH2:12][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 0 °C
Yield: 93.8 %

Procedure:
A solution of 1.08 g of phenylhydrazine and 1.84 g of ethyl 4-oxocyclohexanecarboxylate in 25 ml of acetic acid was refluxed for 30 minutes and then poured into ice water. The aqueous layer was extracted with ethyl acetate. The organic extract was washed thoroughly with a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 50 g of silica gel with a 4:1 v/v mixture of hexane and ethyl acetate as the eluent and then recrystallized from ethyl acetate and hexane, to yield 2.28 g of the title compound, melting at 95°-96° C.
Reaction SMILES: C[O:2][C:3](=[O:65])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][CH:14]=2)=[CH:6][C:5]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[N:42]=[N:43][N:44]([C:46]([C:59]5[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=5)([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)[C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)[N:45]=4)=[CH:40][C:28]=3[N:27]=2)=[CH:22][CH:21]=1.[OH-].[Li+].C1COCC1.Cl>O.C(O)C>[CH:31]1([N:30]2[C:29]3[CH:37]=[CH:38][C:39]([C:41]4[N:42]=[N:43][N:44]([C:46]([C:53]5[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=5)([C:59]5[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=5)[C:47]5[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=5)[N:45]=4)=[CH:40][C:28]=3[N:27]=[C:26]2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:5]3[CH:6]=[C:7]([C:10]4[S:11][C:12]([C:15](=[O:17])[CH3:16])=[CH:13][CH:14]=4)[CH:8]=[CH:9][C:4]=3[C:3]([OH:65])=[O:2])=[CH:25][CH:24]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: COC(=O)c1ccc(-c2ccc(C(C)=O)s2)cc1COc1ccc(-c2nc3cc(-c4nnn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)ccc3n2C2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C(=O)O)c(COc3ccc(-c4nc5cc(-c6nnn(C(c7ccccc7)(c7ccccc7)c7ccccc7)n6)ccc5n4C4CCCCC4)cc3)c2)s1
Yield: 90 %

Procedure:
A mixture of compound 39 (169 mg, 0.19 mmol) and lithium hydroxide (23 mg, 0.97 mmol) in water (1 mL), ethanol (2 mL), and THF (2 mL) was stirred under reflux for 3 h and cooled and acidified with dilute hydrochloric acid to precipitate 40 which was dried in vacuo to afford 147 mg (90% yield). ESI MS m/e 862 (M+1)
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(OC([NH:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])[C:47]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:48]
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)[C@@H](N)C(C)C)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 94, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid give the title compound. LC/MS (M+H)+: 634. Ret. time: 1.42 min. (Condition G); analytical HPLC Ret. time: 6.58 min (Condition Q).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([CH2:32][O:33][CH3:34])[CH2:29][CH2:30]I)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([CH2:32][O:33][CH3:34])[CH2:29][CH2:30][N:10]1[CH2:9][CH:8]([O:7][C:6]2[CH:12]=[CH:13][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:11]1)([CH3:22])([CH3:24])[CH3:23]
Reactant: Clc1ccc(OC2CNC2)cc1
Reactant: COC[C@H](CCI)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC[C@H](CCN1CC(Oc2ccc(Cl)cc2)C1)NC(=O)OC(C)(C)C

Procedure:
A solution of 3-(4-Chloro-phenoxy)-azetidine hydrochloride (0.669 g, 3.04 mmol), triethylamine (1.7 ml, 12.16 mmol) and [(S)-3-Iodo-1-methoxymethyl-propyl)-carbamic acid tert-butyl ester (1.0 g, 3.04 mmol) in dimethylformamide (10 ml) is stirred at ambient temperature for 18 hours, then partitioned between ethylacetate and water. The ethylacetate phase is washed with saturated aqueous sodium bicarbonate solution and brine, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 5:95 methanol/dichloromethane) to afford {(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-carbamic acid tert-butyl ester as a clear oil. [MH]+ 385.25.
Reaction SMILES: [NH2:1][C@H:2]([C@H:4]([OH:20])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:3].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].C(N(CC)CC)C>ClCCl>[CH3:3][C@H:2]1[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[O:20][C:21](=[O:22])[NH:1]1
Reactant: CCCCCCCCCCCCCCC[C@@H](O)[C@H](C)N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCC[C@H]1OC(=O)N[C@H]1C
Reaction time: 5 h

Procedure:
(2S, 3R)-2-amino-3-octadecanol (155, 750 μg, 2.6 μmol) was dissolved in dichloromethane (100 μL) to which 1,1′-carbonyldiimidazole (0.85 mg, 5.3 μmol) and triethylamine (0.4 μL, 2.9 μmol) was added. The solution was stirred for 5 h and then the solvent removed by a stream of nitrogen. The crude product 158 was analyzed without purification: IR (NaCl) 36, 2919, 2851, 1742, 1713, 1551, 1470, 1395, 1321, 49, 1239, 1094, 1061, 1001, 768, 743, 664 cm−1; FABMS m/z 785, 623, 474, 406, 362, 328, 312, 286, 268. Anal. Calcd. For C19H38NO2: 312.2903 (M+H). Found: 312.2903 (HRFABMS).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[NH2:1][C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc(N)cc3)ccc21
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-{5-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (297 mg, 648 μmol) in a mixture of ethanol and water (4:1, 10 mL), was added palladium on carbon (60 mg, 10% w/w Pd) and ammonium formate (245 mg, 3.89 mmol). The resulting suspension was heated to reflux for 2 hours, and was then cooled to room temperature, and filtered through a pad of Celite®. The filtrate was evaporated to dryness, to afford the crude title compound, which was used directly without further purification, [LCMS (Method A, Mobile Phase I) RT=4.04 min, MH+ 430].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[C:13]([O:24]C)[CH:14]=4)=[C:4]2[CH:3]=1.ClC1C=CC2=NC3C4C=CC=CC=4NC4C=3C(C=C(OC)C=4)=C2C=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[C:13]([OH:24])[CH:14]=4)=[C:4]2[CH:3]=1
Reactant: COc1cc2c3c(nc4ccc(Cl)cc4c3c1)-c1ccccc1N2C
Agent: COc1cc2c3c(nc4ccc(Cl)cc4c3c1)-c1ccccc1N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(O)cc1c23
Yield: 88 %

Procedure:
The general procedure (Method K) applied to 3-chloro-6-methoxy-8-methyl-8H-quino[4,3,2-kl]acridine, 32 (5.5 g, 15.9 mmol), with aluminium chloride (6.3 g, 3 eq), and benzene (500 ml) gave the title compound as a yellow solid (4.5 g, 13.5 mmol, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9](I)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[CH:42]=[O:43].C(=O)(O)[O-].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:22]2[S:26][C:25]([C:27]3([O:31][CH2:32][O:33][CH3:34])[CH2:30][CH2:29][CH2:28]3)=[N:24][CH:23]=2)=[C:4]2[CH:10]=[C:9]([C:38]3[CH:39]=[CH:40][C:41]([CH:42]=[O:43])=[C:36]([F:35])[CH:37]=3)[N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Reactant: O=Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4c3cc(-c3ccc(C=O)c(F)c3)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Temperature: 65 °C

Procedure:
To a solution of 5-(5-chloro-2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (580 mg, 0.921 mmol) (Example 1F), 3-fluoro-4-formylphenylboronic acid (309 mg, 1.842 mmol), and bis(triphenylphosphine)palladium dichloride (32.3 mg, 0.046 mmol) in N,N-dimethylformamide (12 ml) was added saturated aqueous sodium bicarbonate solution (12 mL). The mixture was heated to 65° C. under an atmosphere of nitrogen for about 90 minutes. The reaction mixture was cooled to room temperature, and diluted with water (about 50 mL) and saturated brine solution (about 25 mL). The aqueous layer was extracted with ethyl acetate (3×30 mL), and the combined organics were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 30% ethyl acetate in hexane, to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.30 (s, 1H), 8.63-8.60 (m, 1H), 8.23 (s, 1H), 7.95 (t, 1H), 7.81-7.72 (m, 3H), 7.65 (dd, 1H), 7.40 (d, 2H), 7.14 (d, 1H), 4.76 (s, 2H), 2.71-2.54 (m, 2H), 2.35 (s, 3H), 2.01-1.88 (m, 3H). MS APCI(+) m/z 626.42 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].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>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:4]=[N:3][C:2]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:7][CH:6]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(CN1CCN(c2ccc(-c3ccccc3)nn2)CC1)N1CCN(C2CCC2)CC1
Temperature: 85 °C

Procedure:
In a sealed vial, dissolve 3-chloro-6-{4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperazin-1-yl}pyridazine (15.1 mg, 0.04 mmol), phenyl boronic acid (9.8 mg, 0.08 mmol), and Pd(PPh3)4 (2.3 mg, 0.002 mmol) in dioxane (0.7 mL) and 2N K2CO3 (0.1 mL). Degas with N2 and seal the vial. Heat the mixture at 85° C. overnight. Cool and partition between EtOAc (0.5 mL) and 1N NaOH (0.5 mL). Extract the organic phase and place directly on an SCX ion exchange resin cartridge. Wash the resin with EtOAc/MeOH (9:1). Discard this wash. Wash the resin with EtOAc/MeOH/TEA(9:1:1) and collect. Remove the solvent to yield the title compound. 1H NMR (CDCl3) δ 8.00 (dd, 2H) 7.66 (d, 1H), 7.49-7.40 (m, 3H) 6.99 (d, 1H), 3.73 (t, 4H), 3.66-3.63 (m, 4H), 3.26 (s, 2H), 2.75-2.66 (m, 5H), 2.35-2.29 (m, 4H), 1.88-1.84 (m, 2H), 1.74-1.71 (m, 2H) 1.35-1.2 (m, 2H); LC-MS (M+1) 421.05.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=CN=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)C.C([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:8][O:10][C:11](=[O:14])[CH2:12][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:1]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C[C@@H]1CCCO1

Procedure:
A solution of hydroxypyridine 36e (152 g, 0.527 mol), ethylbromoacetate (141 g, 0.843 mol) and Na2CO3 (184.3 g, 1.738 mol) in acetone (2000 mL) is refluxed for 6 h. The aqueous phase is extracted with DCM. The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by chromatography (1-50% EtOAc in petroleum ether) yields ester 36f.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([OH:11])[CH:10]=1)=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[K+].F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9]([O:11][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cncc(O)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
The mixture containing methyl-5-hydroxypyridine-3-carboxylate (1 eq), Potassium bis(trimethylsilyl)amide (1.2 eq) was stirred in N,N-dimethylformamide for 2 hours at room temperature. To this mixture was added 1-fluoro-4-nitrobenzene (1.1 eq) and Potassium carbonate (1.2 eq) and stirred at 80° C. for 16 h. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated in vacuum to give brown solid. Purification on silica gel methyl-5-(4-nitrophenoxy)pyridine-3-carboxylate. MS: MH+=274.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([C:13]#[N:14])[N:3]=1.[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.CCN(CC)CC>CN1C(=O)CCC1>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:13]#[N:14])[N:3]=[C:2]2[NH:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: N#Cc1cc2ccc(Cl)cc2c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccc(Cl)cc23)C1
Temperature: 160 °C
Yield: 79 %

Procedure:
To a solution of 1,7-dichloroisoquinoline-3-carbonitrile (500 mg, 2.24 mmol) in NMP (5 mL) was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (460 mg, 2.46 mmol) and Et3N (453 mg, 4.48 mmol). The solution was heated to 160° C. for 30 minutes in a microwave reactor. The reaction was quenched with H2O (20 mL) and extracted with EtOAc (3×10 mL). The organic layers were combined and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate and petroleum ether (EtOAc/PE=1:10 to 1:5 gradient) to give the title compound (660 mg, 79%). ESI-MS m/z [M+H-tert-butyl]+ 317.