Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[C:3]1([C:44](=[O:46])[NH2:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=1.O.C([O-])([O-])=O.[K+].[K+]>C(O)C>[O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:20])[CH3:21])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[C:3]1([C:44](=[O:46])[NH2:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([OH:41])=[O:40])[CH:34]=1
Reactant: CCOC(=O)c1cccc(C2(C(N)=O)C(=O)N(CC(=O)N(c3ccccc3)C(C)C)c3ccccc3N(c3ccccc3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)N(C(=O)CN1C(=O)C(C(N)=O)(c2cccc(C(=O)O)c2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Yield: 86.4 %

Procedure:
0.12 g of 2-[2,4-dioxo-5-phenyl-3-(3-ethoxycarbonylphenyl)-carbamoyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Example 1, is dissolved in 5 mL of hot ethanol. 2.5 mL of H2O and 0.13 g of K2CO3 are added and the mixture heated at reflux for 4 h and subsequently concentrated in vacuo. The residue is poured into 20 mL of 1N HCl and extracted with ethyl acetate (×3). The organic extract is washed with brine, dried over MgSO4 and concentrated in vacuo to a white solid. Purification by reverse phase C-18 MPLC (70% methanol/TFA-H2O) gave 99 mg of the title compound as a white powder: mp. 165°-170° C.; 1H NMR (CDCl3, 300 MHz) δ8.6 (s, 1H), 8.05 (s, 1H), 7.92 (d, 1H, J=7), 7.75 (d, 1H, J=7), 7.5-7.2 (m, 14H), 7.15 (t, 1H, J=7), 6.97 (d, 1H, J=7), 5.02 (m, 1H), 4.27 (s, 2H), 4.10 (t, 1H, J=7), 3.20 (d, 2H, J=7), 1.08 (d, 3H, J=7), 1.02 (d, 3H, J=7); low resolution MS (FAB) m/e 605 (MH+); Anal. (C35H32N4O6.0.5 TFA.0.5 H2O) Calc. C, 64.5; H, 5.0; N, 8.4; Found: C, 64.5; H, 5.0; N, 8.3.
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:20]=[CH:19][N:18]([C:21]([F:28])([F:27])[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:29][C:30]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[C:31]=1[O:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>C(O)CC>[F:27][C:21]([F:28])([N:18]1[CH:19]=[CH:20][C:16]([S:13](=[O:15])(=[O:14])[NH:12][C:3]2[C:2]([NH:29][C:30]3[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH3:45])[C:31]=3[O:32][CH2:33][CH2:34][CH:35]([OH:37])[CH3:36])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)=[N:17]1)[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]
Reactant: COc1cc(N)c(OCCC(C)O)c(OC)c1
Reactant: CN(C)C(=O)C(F)(F)n1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)n1
Solvent: CCCO
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccn(C(F)(F)C(=O)N(C)C)n2)c(OCCC(C)O)c(OC)c1
Yield: 72.3 %

Procedure:
300 mg of 2-[3-(3-chloroquinoxalin-2-ylsulfamoyl)pyrazol-1-yl]-2,2-difluoro-N,N-dimethylacetamide and 258 mg of 4-(2-amino-4,6-dimethoxyphenoxy)butan-2-ol in 4 ml of 1-propanol are heated at 140° C. in a microwave-suitable glass vessel with high absorption in the microwave until starting material 1 has reacted virtually completely (about 45 minutes). The cooled reaction mixture is filtered off with suction, rinsed with 1-propanol and dried, giving 320 mg of 2,2-difluoro-2-(3-{3-[2-(3-hydroxybutoxy)-3,5-dimethoxyphenylamino]quinoxalin-2-ylsulfamoyl}pyrazol-1-yl)-N,N-dimethylacetamide as slightly yellowish solid (yield 74%). MS-FAB (M+H+)=636.2. Rf (polar method): 2.41 min.
Reaction SMILES: C[Mg]I.Br[C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2.O.[CH3:16]C(OCC)=O>CCOCC.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][N:9]=[CH:10]2
Reactant: Brc1cccc2cnccc12
Reactant: CCOC(C)=O
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: C[Mg]I
Solvent: O
Solvent: CCOCC
Product: Cc1cccc2cnccc12

Procedure:
A 3M solution of methyl magnesium iodide in ether (50 ml, 0.15 mol) was added dropwise to a stirred, ice-cooled solution of 5-bromoisoquinoline (21 g, 0.10 mol), obtained by the method described in J. Org. Chem., 1964, 29, 329, and [1,3-bis(diphenylphosphino)-propane]nickel(II) chloride (400 mg, 0.7 mmol) in anhydrous ether and the reaction mixture heated under reflux for 5 days, allowed to cool, then poured into water (500 ml). The organic phase was separated, combined with ether extracts of the aqueous phase, washed with saturated brine, dried (MgSO4) and evaporated under reduced pressure to yield an oil, chromatography of which on silica gel, using a 5-50% ether in hexane elution gradient, provided the required. product (8.4 g). Rf 0.40 (SS 8), m/e 144 (M+H)+. Found: C,79.57; H,6.26; N,8.61. C10H9N; 0.27 CH3CO2CH2CH3 requires C,79.70; H,6.74; N,8.39%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=1)[CH2:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=Cc1nccc2ccccc12
Reactant: Cc1cnc(CNCCCCN(C)C(=O)OC(C)(C)C)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN(C)C(=O)OC(C)(C)C)Cc2nccc3ccccc23)c(C)c1

Procedure:
Using General Procedure B: Reaction of {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester and 1-isoquinoline-carbaldehyde with NaBH(OAc)3 in CH2Cl2 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a yellow oil.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[NH:29][C:28]=2[C:36]([NH2:38])=[O:37])=[CH:23][CH:22]=1.[C:39]([C:43]1[CH:44]=[C:45]([NH2:55])[N:46]([C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)[N:47]=1)([CH3:42])([CH3:41])[CH3:40]>O1CCCC1>[C:39]([C:43]1[CH:44]=[C:45]([NH:55][C:5](=[O:11])[NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][C:28]=3[C:36]([NH2:38])=[O:37])=[CH:25][CH:26]=2)[N:46]([C:48]2[CH:49]=[CH:50][C:51]([CH3:54])=[CH:52][CH:53]=2)[N:47]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: NC(=O)c1[nH]c2ccccc2c1-c1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 204.3 %

Procedure:
43 mg of triphosgene followed by 110 μl of triethylamine at 0° C. are added to a solution of 100 mg of 3-(4-aminophenyl)-1H-indole-2-carboxamide (example 1) in 18 ml of tetrahydrofuran. The mixture is stirred for one hour at ambient temperature and then 110 mg of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine are added. The mixture is stirred for one hour and concentrated under reduced pressure, and the residue is triturated with 2 ml of ethyl acetate, to give a white solid. After filtration and drying, 150 mg of 3-{4-[3-(5-tertbutyl-2-p-tolyl-2H-pyrazol-3-yl)ureido]phenyl}-1H-indole-2-carboxamide are obtained, the characteristics of which are as follows:
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40].[O:43]1CC[CH2:45][CH2:44]1>>[C:39]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH:1][C:44](=[O:43])[CH3:45])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:41])[CH3:40]
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O
Reactant: CC(=O)Cl
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 1.94 parts of N,N-diethylethanamine. After cooling to 0° C., 1.4 parts of acetyl chloride dissolve in 9 parts of tetrahydrofuran were added dropwise at a temperature below 0° C. Upon completion, stirring was continued for a while in an ice-bath. The mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The solvent was evaporated and the residue was taken up in a saturate sodium carbonate solution. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated. The residue was purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was suspended in petroleumether. The product was filtered off and dried, yielding 0.59 parts of cis-4-[[4-(acetylamino)-5-chloro-2-methoxybenzoyl]amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 172.2° C. (compound 231).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[CH3:14][C:15]1[C:19](B(O)O)=[C:18]([CH3:23])[O:17][N:16]=1.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[CH3:14][C:15]1[C:19]([C:5]2[CH:4]=[N:3][C:2]([NH:24][C:25]3[S:26][CH:27]=[C:28]([CH3:30])[N:29]=3)=[C:11]3[C:6]=2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[C:18]([CH3:23])[O:17][N:16]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Cc1csc(N)n1
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Product: Cc1csc(Nc2ncc(-c3c(C)noc3C)c3ccc(C)nc23)n1

Procedure:
The title compound, MS: m/e=352.3 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I), 3,5-dimethyl-isoxazole-4-boronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-:6])O.[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:29](=[O:48])[N:30]([CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C:31]3[N:32]([N:37]=[CH:38][N:39]=3)[C:33]=2[CH2:34][CH2:35][CH3:36])=[CH:23][CH:22]=1)#[N:14]>C(OCC)(=O)C>[O:48]=[C:29]1[C:28]([CH2:27][C:24]2[CH:23]=[CH:22][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:13]3[NH:3][C:4](=[O:7])[O:6][N:14]=3)=[CH:26][CH:25]=2)=[C:33]([CH2:34][CH2:35][CH3:36])[N:32]2[N:37]=[CH:38][N:39]=[C:31]2[N:30]1[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)OC(C)(C)C)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogen carbonate (2.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, tert-butyl {6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}acetate (0.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.32 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.73 g, 82%).
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+]>>[C:3]([CH:2]([NH:14][C@H:15]([C:23]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27]([OH:29])=[O:28])=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([OH:5])=[O:4]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: O=C(O)C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
In the manner described in example 24, 2-oxo-4-phenylbutyric acid and L-phenylalanyl-L-proline are condensed in the presence of sodium cyanoborohydride to yield N-(1-carboxy-3-phenylpropyl)-L-phenylalanyl-L-proline.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:21])[CH:18]=[N:19][CH:20]=3)[S:15][C:8]=12.[CH3:22][C:23]([CH3:25])=[O:24]>O1CCCC1.O>[Cl:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:21])[C:18]([C:23]([OH:24])([CH3:25])[CH3:22])=[N:19][CH:20]=3)[S:15][C:8]=12
Reactant: Cn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(-c2cc3nccc(Cl)c3s2)cnc1C(C)(C)O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31 %

Procedure:
In a 50 mL round-bottomed flask 7 mL of tetrahydrofuran and n-butyllithium (0.88 mL, 2.5M in hexane) were cooled to −40° C. A suspension of 7-chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine (500 mg, 2.00 mmol) in 9 mL of tetrahydrofuran was added dropwise to the solution and stirred for 40 minutes. Acetone (0.79 mL, 3.00 mmol) was added to the anion and the reaction mixture was allowed to warm to room temperature overnight. The mixture was diluted with water and extracted with chloroform (3×50 mL). The combined extracts were dried over NaSO4, filtered, and concentrated. Chromatography on 50 g of silica gel with 5% methanol:methylene chloride afforded 191 mg (31%) of 2-[5-(7-chloro-thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-2-yl]-propan-2-ol. 1H NMR (400 MHz, CDCl3) δ8.58 (d, 1H), 7.51 (s, 1H), 7.28 (d, 1H), 7.24 (s, 1H), 4.02 (s, 3H), 1.77 (s, 6H). LC-MS: 308.1, 310.1 (MH+); HPLC RT: 4.18 min.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2.CCOCC>COCCOCCOC>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:2]3[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=3[C:4]([O:6][CH3:7])=[O:5])[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1Oc1cccc2[nH]ccc12

Procedure:
Methyl 2,4-difluorobenzoate (1.53 g), K3PO4 (1.89 g) and 4-hydroxyindole (1.08 g) were stirred at 110° C. in diglyme (12 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M aqueous NaOH solution, and brine, and dried over Na2SO4. The solution was then concentrated, and the crude product was chromatographed on silica gel with 20% ethyl acetate/hexanes.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[N:15][C:16]([NH:20][CH2:21][C:22]([NH2:24])=O)=[CH:17][N:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].O=P(Cl)(Cl)Cl>C(Cl)Cl.CO>[S:1]([N:11]1[C:19]2[N:18]=[CH:17][C:16]3[N:15]([C:22]([NH2:24])=[CH:21][N:20]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(N)=O)cnc32)cc1
Solvent: CO
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(N)n23)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 42.8 %

Procedure:
To 2-(5-tosyl-5H-pyrrolo[3,2-b]pyrazin-2-ylamino)acetamide (0.845 g, 2.45 mmol, prepared using E from Preparation #S.1.1 and HCl) under nitrogen was added POCl3 (5.0 mL, 54 mmol). After about 15 min, a reflux condenser was attached and the mixture was warmed to about 100° C. After about 2 h, the solution was allowed to cool to ambient temperature. The mixture was concd under reduced pressure. The residue was slurried in DCM (10 mL) and slowly treated with MeOH (10 mL). The reaction mixture was stirred for about 5 min then concd under reduced pressure. The residue was dissolved in MeOH (20 mL) and then concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (5 mL) and 2N aqueous HCl (5 mL). The solution was warmed to about 100° C. for about 3 h. The solution was allowed to cool to ambient temperature and the volatiles were removed under reduced pressure. The aqueous mixture was slurried in saturated aqueous NaHCO3/water (1:1, 100 mL) and DCM (50 mL). The solid was collected by filtration, rinsed with water and DCM, and dried to afford 3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-amine (0.343 g, 43%): LC/MS (Table 1, Method n) Rt=0.56 min; MS m/z: 328 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.O[CH2:40][CH2:41][CH:42]1[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:40][CH2:41][CH:42]1[CH2:43][CH2:44][N:45]([C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49])[CH2:46][CH2:47]1)[CH:5]=2
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reaction time: 2 h

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 36 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, t-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate instead of 4-(2-hydroxyethyl)morpholine, being stirred for 2 h, and being purified by silica gel column chromatography (EtOAc/hexanes=1:3) to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][C:11]2[C:12]([F:29])=[C:13]([CH2:18][NH:19][C:20]([C:22]3[NH:26][C:25]([CH3:27])=[N:24][C:23]=3[Cl:28])=[O:21])[CH:14]=[CH:15][C:16]=2[Cl:17])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[CH:30]([B-](F)(F)F)=[CH2:31].[K+]>C(O)CC.CCOC(C)=O>[Cl:28][C:23]1[N:24]=[C:25]([CH3:27])[NH:26][C:22]=1[C:20]([NH:19][CH2:18][C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([O:10][C:4]2[CH:3]=[C:2]([CH:30]=[CH2:31])[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=2)[C:12]=1[F:29])=[O:21]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Br)cc(C#N)c3)c2F)[nH]1
Agent: [K+]
Solvent: CCCO
Solvent: CCOC(C)=O
Product: C=Cc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C)nc3Cl)c2F)c1
Temperature: 100 °C
Yield: 61.3 %

Procedure:
To a solution of N-({3-[(3-bromo-5-cyanophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-2-methyl-1H-imidazole-5-carboxamide (0.480 g, 0.964 mmol), potassium vinyltrifluoroborate (0.194 g, 1.445 mmol) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.079 g, 0.096 mmol) in n-propanol (8 ml) was added TEA (0.672 ml, 4.82 mmol) and the reaction mixture was heated at 100° C. for 4 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-2-methyl-1H-imidazol e-5-carboxamide (0.263 g, 0.591 mmol, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.05 (t, 1H), 7.77 (s, 1H), 7.47 (d, 1H), 7.40 (br. s., 1H), 7.32 (t, 1H), 7.26 (br. s., 1H), 6.72 (dd, 1H), 6.01 (d, 1H), 5.41 (d, 1H), 4.51 (d, 2H), 2.23 (s, 3H).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:1][NH:2][C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])(=[O:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)ONC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
The starting material is prepared as follows: tert-Butyl N-hydroxycarbamate (3.89 g, 29.2 mmol) is dissolved in 25 ml of dichloromethane and cooled to 0° C. To this is added triethylamine (3.25 g, 32.1 mmol) and acetyl chloride (2.29 g, 29.2 mmol) dropwise. The mixture is extracted with ether and the extracts are washed with aqueous 2N HCl, water, 10% sodium bicarbonate, water, dried (MgSO4) and evaporated. The resulting colorless oil is purified by silica gel chromatography (10% ethyl acetate/hexane) to give O-acetyl-N-tert-butoxycarbonylhydroxylamine as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[N-:13]=[N+]=[N-].[Na+].CS(O)(=O)=O.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:13][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a mixture of 6-Methoxy-1-indanone (15 g, 92.6 mmol), sodium azide (26.7 g, 277.8 mmol), in CHCl3 was added methane sulfonic acid (60 g, 926 mmol) via addition funnel at 0° C. Reaction mixture was warm to room temperature. Stirring was continued for 3 hr, then poured into cold water. The organics were extracted with methylene chloride and washed with water, sat. NaCl and dried over Na2SO4. Organic solution was concentrated in vacuo and the residue was purified with silica gel eluting with 20% EtOAc/Hexane to give the title compound as a yellow solid (10.5 g, 63%). MS (ES) m/z 178.1.
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16]1(=[O:22])[O:21][C:19](=[O:20])[CH2:18][CH2:17]1>ClCl>[C:1]1([CH2:14][O:15][C:16](=[O:22])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCc1cccc2c1Cc1ccccc1-2
Reactant: O=C1CCC(=O)O1
Agent: ClCl
Product: O=C(O)CCC(=O)OCc1cccc2c1Cc1ccccc1-2
Reaction time: 6 h

Procedure:
Fluorenemethanol (10.0 g, 51.0 mmol) was dissolved in 150 ml CH2 Cl2, and succinic anhydride (5.6 g, 56 mmol) was added. The solution was stirred for 6 h, and a further portion of succinic anhydride (2.5 g, 25 mmol) was added, and stirring continued overnight. The reaction appeared complete by TLC. The solvent was then removed, and the residue extracted with ethyl acetate, washed with 1% HCl, water, brine, dried (MgSO4) and evaporated to an oil which crystallized on standing. A quantitative yield of crude product was obtained which was used without further purification.