Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH:16]1[C:33]2[C:20](=[CH:21][C:22]3[C:31]([CH:32]=2)=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=3)[CH:19]=[CH:18][CH:17]=1>ClC1C=CC=CC=1Cl>[CH:19]1[C:20]2[C:33](=[C:32]([CH:9]=[O:10])[C:31]3[C:22]([CH:21]=2)=[CH:23][C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=3)[CH:16]=[CH:17][CH:18]=1
Reactant: CN(C=O)c1ccccc1
Reactant: c1ccc2cc3cc4ccccc4cc3cc2c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: O=Cc1c2ccccc2cc2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 31 %

Procedure:
To a 3-necked RB flask equipped with overhead mechanical stirrer, condenser, addition funnel, N2 inlet line with bubbler was added n-methylformanilide (Aldrich 89.21 g, 0.66 mol, 81 mL) and o-dichlorobenzene (Aldrich, 200 mL). The mixture was cooled to 10° with an ice bath. Phosphorus oxychloride (Aldrich, 101.21 g, 0.66 mol, 60 mL) was then added dropwise to the solution not allowing the reaction temperature to rise above 10°. The reaction mixture was then allowed to warm to RT. Solid naphthacene (Cambridge Chemical, Inc., 50 g, 0.22 mol) was then added in five portions over 5 min. The reaction mixture was warmed slowly to 80° (the mixture turns from purple to an almost black color). The reaction was stirred at 80° for 12 h, cooled, poured into ice water (2 L) and stirred an additional 12 h at RT. The mixture was then filtered. The organic layer in the filtrate was dried (Na2SO4) and applied to a plug of SiO2 (500 g) and eluted first with PhCH3 followed by CH2Cl2. The appropriate fractions were combined and the solvent removed by rotary evaporation. Recrystallization (CH2Cl2 /EtOAc) gave 17.5 g (31.1% yield) of naphthacene-5-carbaldehyde, mp 163°-164° (Lit. 164°, N. P. Buu-Hoi et al., Recueil 76 674 (1957)), (C,H). The solid from the filtration of the crude reaction mixture was washed with a large volume of CH 3 OH (5×200 mL), dissolved in THF (4 L) and passed through a plug of SiO2 (500 g) using an additional 2 L of THF as eluting solvent. The solvent was reduced to a volume of 300 mL and then diluted to 800 mL with EtOAc. The solvent volume was reduced to 250 mL. After filtration and drying 10.90 g (17.4% yield) of naphthacene-5,11-dicarbaldehyde, mp 247°-250°, (C,H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:27]([O:31][C:32](=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:27]([O:31][C:32](=[O:43])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:18](=[O:19])[CH:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:37]([F:42])[CH:36]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)CCc1ccc(N)c(F)c1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCc1ccc(NC(=O)C(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1

Procedure:
In analogy to the procedure described in example 59, [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (example 5.1) was reacted with 3-(4-amino-3-fluoro-phenyl)-propionic acid tert-butyl ester in the presence of DIPEA and HATU in DMF to give the title compound yellow solid.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1)=[O:11])[CH3:8].[OH:19][C:20]([CH3:53])([CH3:52])[CH2:21][C@@:22]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[O:27][C:26](=[O:28])[N:25]([C@H:29]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH3:30])[CH2:24][CH2:23]1>CN(C)C=O>[CH2:7]([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:34]2[CH:33]=[CH:32][C:31]([C@@H:29]([N:25]3[CH2:24][CH2:23][C@:22]([CH2:21][C:20]([OH:19])([CH3:52])[CH3:53])([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[O:27][C:26]3=[O:28])[CH3:30])=[CH:36][CH:35]=2)[N:13]=1)=[O:11])[CH3:8]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2 M aqueous Na2CO3 solution (1.46 mL) was added to a mixture of 6-bromo-pyridine-2-carboxylic acid ethyl ester (0.50 g) and (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.70 g) in N,N-dimethyl-formamide (8 mL). The resulting mixture was sparged with argon for 10 min, before [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro-palladium(II) dichloromethane complex (72 mg) was added. The mixture was heated to 100° C. and stirred at this temperature overnight. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and the solvent was evaporated. The residue was purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the title compound. Yield: 0.59 g (80% of theory); Mass spectrum (ESI+): m/z=503 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[CH2:28])[CH2:5][O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[CH:34]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:34][C:33]3[CH:36]=[C:37]([O:41][CH3:42])[C:38]([O:39][CH3:40])=[C:31]([O:30][CH3:29])[CH:32]=3)[C:7]([O:6][CH2:5][C:4]([CH3:3])=[CH2:28])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(C)COc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-(2-methylallyloxy)-8-acetyl-3-methylflavone (2.61 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 82-84° C., 1H-NMR (CDCl3) δ:1.76 (s, 3H); 2.20 (s, 3H); 3.82 (s, 3H); 4.62 (s, 2H); 5.05 (d, 2H, J=18 Hz); 6.95-7.10 (m, 3H); 7.09 (d, 1H); 7.10 (d, 1H, J=9 Hz); 7.31 (d, 1H, J=16 Hz); 7.40-7.45 (m, 3H); 7.55-7.58 (m, 2H); 7.31 (s, 2H); 8.32 (d, 1H, J=8.9 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:18]3[CH2:19][CH2:20][NH:21][C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)=[CH:5][CH:4]=1.[C:22]([NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[C:37](O)=[O:38])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.CCOC(OC(OCC)=O)=O>CN(C=O)C>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@H:18]3[CH2:19][CH2:20][N:21]([C:37]([C@H:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]4[NH:30][C:22](=[O:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:38])[C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)=[CH:7][CH:8]=1
Reactant: O=C(N[C@@H]1CCCC[C@@H]1C(=O)O)c1ccccc1
Reactant: CSc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1ccc([C@@H]2Nc3ccccc3[C@H]3[C@@H]2CCN3C(=O)[C@H]2CCCC[C@H]2NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.5 %

Procedure:
To a suspension of (3aS,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline (1.10 g, 3.0 mmol) and (1S,2R)-2-(benzoylamino)cyclohexanecarboxylic acid (0.74 g, 3.0 mmol) in DMF (20 ml) were added under ice-cooling, triethylamine (0.91 g, 9.0 mmol), and then a solution of DEPC (0.49 g, 3.0 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for 16 hrs., the reaction mixture was poured into ice water and the mixture was extracted with diethyl ether. The extract was washed with saturated brine, dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (2:1-1:1, v/v) to give N-[(1R,2S)-2-({(3aR,4R,9bR)-4-[4-(methylthio)phenyl]-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl}carbonyl)cyclohexyl]benzamide (0.45 g, 29%) from the first eluted fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]=[C:5]2[CH:13]1[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:32][C:31]1[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=1)[C:7](=[O:12])[N:6]=[C:5]2[CH:13]1[CH2:15][CH2:14]1
Reactant: O=c1nc(C2CC2)c2cc(Cl)ccc2[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(Cn2c(=O)nc(C3CC3)c3cc(Cl)ccc32)cc1
Reaction time: 8 h
Yield: 51.3 %

Procedure:
To a 0° C. solution of 9.0 g (0.04 1 mol) of 6-chloro-4-cyclopropylquinazolin-2(1H)-one in 150 mL of dry DMF (Aldrich Sure-Seal) under Ar was added 42.5 mL of a 1.0M solution of lithium bis(trimethylsilyl)amide in hexane dropwise. After the addition, 8.14 mL (0.06 mol) of p-methoxybenzyl chloride (Aldrich) was added in one portion, and the flask immersed in an oil bath maintained at 55°-60° C. The reaction was heated for 12.5 h, then allowed to stand at room temperature overnight. The solvents were removed by rotovap at reduced pressure and the residue partitioned between CHCl3 and cold 1M citric acid. The aqueous layer was extracted with CHCl3 and the combined organic layers washed with 10% Na2CO3, dried over MgSO4. After removal of the solvents by rotovap at reduced pressure, the residue was triturated with ether to give 10.5 g (75%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]([NH2:23])=O)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.O.[NH2:25][NH2:26].[C:27]([OH:30])(=[O:29])[CH3:28]>COC(OC)(N(C)C)C>[C:27]([OH:30])(=[O:29])[CH3:28].[CH3:1][C:2]1[C:9]([C:10]2[S:11][C:12]([C:21]3[NH:23][C:27]([CH3:28])=[N:26][N:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=2)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: NN
Reactant: Cc1nn2ccsc2c1-c1nc(-c2ccccc2)c(C(N)=O)s1
Agent: COC(C)(OC)N(C)C
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(-c2sc(-c3c(C)nn4ccsc34)nc2-c2ccccc2)[nH]1
Temperature: 90 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
2-(6-Methylpyrazolo[5,1-b][1,3]thiazol-7-yl)-4-phenyl-1,3-thiazole-5-carboxamide (79 mg, about 0.23 mmol) produced in the same manner as in Example 35-B(ix) was suspended in N,N-dimethylacetamide dimethyl acetal (2 mL), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, hydrazine monohydrate (0.017 mL, 0.35 mmol) and acetic acid (2 mL) were added to the residue, and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and the resulting solid was collected by filtration and washed with ethyl acetate to give the title compound (72 mg, 70%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](B(O)O)=[CH:4][CH:3]=1.[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[N:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>O>[CH3:15][C:16]1[NH:17][C:18]([CH3:28])=[CH:19][C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)[N:22]=1
Reactant: Cc1cc(-c2cccc(Br)n2)c(C)[nH]1
Reactant: OB(O)c1ccc(F)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(-c2cccc(-c3ccc(F)c4ccccc34)n2)c(C)[nH]1
Yield: 700.4 %

Procedure:
To a 50 mL round-bottomed flask equipped with condenser and N2 inlet were added 404 mg (2.13 mmol) 4-fluoronaphthalene-1-boronic acid, 534 mg (2.13 mmol) 2-(2,5-dimethylpyrrolyl)-6-bromopyridine, 902 mg (8.51 mmol) sodium carbonate, 150 mg tetrakistriphenylphosphine, 10 mL ethanol, and 2 mL water. The reaction was refluxed overnight, cooled, poured into water, and extracted into ethyl acetate. After combining with another run on a larger scale, the combined organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using hexane/ethyl acetate as eluant to afford 4.72 g (85%) of an oil.
Reaction SMILES: [Br-].[C:2]([CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[OH-].[Na+].[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1>O.C(Cl)Cl>[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[C:30]([CH:40]=[CH:41][CH:42]=1)[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:4][C:2]#[N:3])=[CH:34][CH:33]=1
Reactant: N#CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#CC=Cc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.9 %

Procedure:
To a solution of (cyanomethyl)triphenylphosphonium bromide (8.61 g, 22.54 mmol) and NaOH (1.127 g, 28.2 mmol) in water (24 mL) and DCM (12 mL) was added 4-(3-(trifluoromethyl)phenoxy)benzaldehyde (5 g, 18.78 mmol) at 0° C. The mixture was stirred at room temperature for 4 h. DCM (50 mL) and water (50 mL) was added to the mixture, the organic phase was washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated. Purification via flash chromatography afforded the title compound (5.07 g, 17.26 mmol, 92% yield) as pale yellow oil (slowly solidify to white solid). LCMS: rt=1.67 min, [M+H+]=290
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=4)[CH:24]=3)(=[O:22])=[O:21])[CH2:16][C:17]([OH:19])=O)[C:11]2=[O:35])[CH:6]=[CH:5][N:4]=1)#[N:2].[CH2:36]([NH2:44])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([N:15]([S:20]([C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]([O:33][CH3:34])=[CH:28][CH:29]=4)[CH:24]=3)(=[O:21])=[O:22])[CH2:16][C:17]([NH:44][CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:19])[C:11]2=[O:35])[CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: NCCc1ccccc1
Reactant: COc1ccc2ccc(S(=O)(=O)N(CC(=O)O)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(CC(=O)NCCc3ccccc3)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 127, Part C using 2-[[1-(2-cyan-pyridine-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxy-naphthalene-2-sulfonyl)amino]acetic acid in place of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(7-methoxynaphthalene-2-sulfonyl)amino-]acetic acid and with phenethylamine instead of NH4OH. The crude product is purified by column chromatography eluting with gradient of 50% EtOAc/CH2Cl2 to 2% MeOH/50% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([CH2:41]O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:41]([O:15][C:14](=[O:16])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 95.1 %

Procedure:
(S)-6-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)-hexanoic acid (5.00 g, 10.67 mmol) and phenyl-methanol (2.305 g, 21.34 mmol) were dissolved in 25 mL of CH2Cl2 and treated successively with N-hydroxybenzotriazole (1.933 g, 11.74 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 2.250 g, 11.74 mmol), and ethyl-diisopropyl-amine (2.137 ml, 12.49 mmol). After stirring for 90 min, the volatiles were removed i.V. at ambient temperature, the residue taken up in ethyl acetate, washed with water, NH4Cl-solution and brine, dried over Na2SO4, and evaporated. The crude mixture was then dissolved in 20 mL of ethanol, and the product precipitated by adding 10 mL of water. Filtration and drying yielded 5.669 g of the title compound which was recrystallized from ethanol/hexane to give 4.27 g of pure benzyl ester. MS (ISP): 559.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:11]([O:12][CH3:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2
Reactant: O=Cc1ccc2c(Br)c(O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc2cc(C=O)ccc2c1Br
Yield: 96 %

Procedure:
Step c) A mixture of 5-bromo-6-hydroxy-2-naphthaldehyde (34.0 g, 135.5 mmol), potassium carbonate (18.7 g, 135.5 mmol), dimethyl sulfate (12.8 mL, 135.5 mmol) and acetone (500 mL), was refluxed for 3 hours. The volatiles were removed in vacuo, and the residue was suspended in water. The precipitated solid was filtered and dried, to yield a yellow solid (34.5 g, 96% yield, m.p. 133°-135° C.).
Reaction SMILES: [C:1]1([N:13]2[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OC(C)(C)C)[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1.Cl.CCN(C(C)C)C(C)C.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][S:39]([CH:36]3[CH2:38][CH2:37]3)(=[O:41])=[O:40])[CH2:14]2)[N:5]2[C:6]3[CH:12]=[CH:11][NH:10][C:7]=3[N:8]=[CH:9][C:4]2=[CH:3][N:2]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ncc3cnc4[nH]ccc4n23)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(NC1CCN(c2ncc3cnc4[nH]ccc4n23)C1)C1CC1
Reaction time: 4 h
Yield: 70.6 %

Procedure:
To a solution of tert-butyl 1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-ylcarbamate (0.175 g, 0.511 mmol, Example #D.1.42) in DCM (10 mL) was added HCl (4 N in 1,4-dioxane, 1.28 mL, 5.11 mmol). After about 4 h at ambient temperature, the reaction mixture was concd in vacuo. The residue was suspended in DCM (10 mL) and DIEA (0.446 mL, 2.56 mmol) was added to the reaction mixture resulting in a nearly homogeneous mixture. To the mixture was added cyclopropanesulfonyl chloride (0.079 g, 0.56 mmol). After about 2 h at ambient temperature, additional cyclopropane-sulfonyl chloride (0.079 g, 0.56 mmol) was added. After about 6 h at ambient temperature, saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were concd in vacuo and purified by chromatography on silica gel (40 g) eluting with 50-90% MeCN in DCM to provide N-(1-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)pyrrolidin-3-yl)cyclopropane-sulfonamide (0.125 g, 70%) as a tan solid: LC/MS (Table 1, Method a) Rt=1.42 min; MS m/z: 347 (M+H)+.
Reaction SMILES: [Cl-:1].[Na+].[C:3]12([CH2:13][C:14]([OH:16])=[O:15])[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([CH2:6]3)[CH2:4]1)[CH2:10]2.S(=O)(=O)(O)O>C(Cl)(Cl)(Cl)Cl.C(O)(C)(C)C>[C:14]([CH2:13][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([Cl:1])([CH2:6]3)[CH2:4]1)[CH2:10]2)([OH:16])=[O:15]
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: [Cl-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)CC12CC3CC(CC(Cl)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
18 Grams of sodium chloride were added in about 20 equal portions to a mixture of 3 g of 1-adamantyl-acetic acid, 60 ml. of carbon tetrachloride and 200 g of 96% sulfuric acid which was kept at 5° -10°C by external cooling under thorough stirring over a period of 6 hours while a mixture of 9 g of t-butanol and 20 ml. of carbon tetrachloride was added thereto dropwise over 30 minutes. The reaction mixture was poured onto 300 g of broken ice pieces. The crystalline precipitate was filtered out, washed with water sufficiently and air-dried to obtain 3.2 g (yield: 91.1%) of crude 1-carboxymethyl-3-chloroadamantane.
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]([CH3:35])[C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:30]3[N:29]=[C:28]([CH3:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=1)(O)=O.C1(P([N:50]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>O1CCOCC1>[NH2:50][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]([CH3:35])[C:12](=[O:34])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]2[C:30]3[N:29]=[C:28]([CH3:31])[NH:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[O:21])=[C:15]([O:32][CH3:33])[CH:14]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2C(=O)O)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2N)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Temperature: 80 °C
Yield: 85.2 %

Procedure:
A mixture of N-(2-carboxy-4-methylphenyl)-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylamino-benzamide (350 mg), diphenylphosphorylazide (224 mg) and triethylamine (82.5 mg) in dioxane (10 mg) was heated at 80° C. for 6 hours. After evaporation, the residual oil was subjected to silica gel column and the column was eluted with 5% methanol in chloroform. Object fractions were collected and evaporated in vacuo and the residue was solidified from chloroform to give N-(2-amino-4-methylphenyl)-3-methoxy-N-methyl-4-(2-methyl-1-H-benzimidazol-4-yl)carbonylamino-benzamide (280 mg).