Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:36])[C:25]#[CH:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]3=[O:36])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CCN1Cc2ccccc2C1=O
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1F)=NC2
Product: Cc1nnc2n1-c1ccc(C#CCN3Cc4ccccc4C3=O)cc1C(c1ccccc1F)=NC2

Procedure:
Reaction of 6-(2-fluorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 2,3-dihydro-(2-propynyl)-1H-isoindol-1-one [ref. J. I. Neumeyer, U. V. Moyer, J. A. Richman, F. J. Rosenberg and D. G. Teiger, J. Med. Chem. 10, 615 (1967)] gave after chromatographic purification as described in example 17 and crystallization from ethyl acetate colorless crystals of the title compound with m.p. 165°-168° C. According to spectral and analytical data, these crystals contained 0.5 molar amounts of water and traces of ethyl acetate.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18](F)[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(O)=[O:28].[Na+]>C(O)=O>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([OH:28])[CH:17]=4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:23])[C:8](=[O:24])[C@H:7]2[CH2:25][CH3:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(F)c3)nc2N1C1CCCC1
Agent: [Na+]
Solvent: O=CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccnc(O)c3)nc2N1C1CCCC1
Yield: 80 %

Procedure:
(R)-8-cyclopentyl-7-ethyl-2-(2-fluoropyridin-4-yl)-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 16, 100 mg, 0.28 mmol) was dissolved in 3 mL of HCOOH. This mixture was heated to reflux for 18 h, then aqueous NaHCO3 was added and the mixture was extracted with EtOAc. The combined organic phase was dried with Na2SO4, concentrated under reduced pressure and chromatographed on flash silica gel (CH2Cl2:CH3OH=6:1) to give the title compound as a white solid (80 mg, 80% yield). 1H NMR (CD3OD) δ: 8.09 (s, 1H), 8.52 (d, 1H) 7.46 (s, 1H), 7.27 (m, 1H), 4.42-4.38 (m, 2H), 3.41 (s, 3H), 2.0-1.7 (m, 10H) and 0.86 ppm (t, 3H); LCMS: 354.2 m/z (M+H)+; ret. Time: 1.36 min (Analytical Method E).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nnn[nH]2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(-c2nnn[nH]2)c1
Reaction time: 2 h

Procedure:
3-Nitro-(1H-tetrazol-5-yl)benzene was dissolved in 200 ml of ethanol, treated with 1.7 g of 10% palladium/carbon catalyst, and hydrogenated on a Parr apparatus at 30 psi for 2 hours. The reaction mixture was filtered through Celite and concentrated to give 4.7 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:13]2[C:21]3[C:16](=[CH:17][C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][N+:10]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+].CCOC(C)=O>C1COCC1.CO.[Zn]>[NH2:10][CH2:9][CH:8]([C:7]1[C:2]([CH3:1])=[C:3]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:4]=[CH:5][CH:6]=1)[C:13]1[C:21]2[C:16](=[CH:17][C:18]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:19][CH:20]=2)[NH:15][CH:14]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(C[N+](=O)[O-])c1c[nH]c2cc(N3CCOCC3)ccc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCOCC3)ccc12
Yield: 84.6 %

Procedure:
A heterogeneous solution of benzyl 2-methyl-3-(1-(6-morpholino-1H-indol-3-yl)-2-nitroethyl)phenylcarbamate (1.8743 g, 3.64 mmol), ammonium chloride (2.92 g, 54.6 mmol) and zinc (3.57 g, 54.6 mmol) in THF (Ratio: 1.000, Volume: 79 ml) and methanol (Ratio: 1.000, Volume: 79 ml) was stirred under nitrogen for 2.5 hr. EtOAc (60 mL) was added, and the solution was filtered through a pad of CELITE®. The filtrate was concentrated in vacuo; the residue was dissolved in water (50 mL) and EtOAc (75 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (2×75 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the desired product (1.4934 g, 3.08 mmol, 85% yield) as a tan solid.
Reaction SMILES: P(=O)(O)(O)O.[C:6]1([CH3:33])[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:21]=[C:20]([C:22]([OH:24])=O)[C:19]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[CH:18][C:14]=2[C:15](O)=[O:16])=[CH:8][CH:7]=1>O>[CH3:32][C:29]1[CH:28]=[CH:27][C:26]2[NH:25][C:19]3[C:20]([C:22](=[O:24])[C:31]=2[CH:30]=1)=[CH:21][C:13]1[NH:12][C:9]2[CH:8]=[CH:7][C:6]([CH3:33])=[CH:11][C:10]=2[C:15](=[O:16])[C:14]=1[CH:18]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 40 °C
Reaction time: 0.75 h
Yield: 15 %

Procedure:
Two hundred ml of polyphosphoric acid and 100 ml of 85% phosphoric acid are mixed in a mechanically stirred beaker and allowed to cool to 40° C. Thirty grams of 2,5-di(p-tolylamino)terephthalic acid (DTTA) are added in small portions, successively, under intense agitation by Gifford-Wood homogenizer. Care is taken to dissolve each portion before adding another one. The temperature is kept below 60° C. by external water bath cooling. After having dissolved all of the DTTA, as ascertained by dipping a glass rod into the viscous reaction medium and examining for solid particles clinging to the rod, the solution is transferred into a 500 ml round-bottom flask equipped with mechanical stirrer, CaSO4 drying tube, N2 inlet and thermometer, and heated to 100° C. within 45 minutes with stirring. The temperature is held at 100° C. for 45 minutes. The solution develops an orange-brown fluorescense during this time. The solution is poured into 2 l of water with mechanical stirring, generating a dark-colored precipitate. Stirring is continued for 10 minutes. The precipitate is filtered, washed acid-free with water and suspended in 2 l of H2O. The suspension is made basic with a pH of 12 by adding 50 wt % aqueous NaOH solution with stirring, is heated, kept at 60° C. for 15 minutes with continued stirring and filtered while warm. The filter cake is washed with water and dried in a vacuum oven at 70°-80° C. to give 4.0 g (15% yield) of apparently 2,9-dimethylquinacridone by-product. The filtrate and wash water combined are acidified with acetic acid to a pH of 4, with stirring. The resulting red precipitate is filtered, washed acid-free with water and dried overnight at 70°-80° C. under vacuum and slight N2 purge to give 22.3 g (78% yield) of red 2-(p-tolyl)amino-3-carboxy-7-methyl-9(10H)acridinone (TMCA).
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([OH:16])=O)[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[CH3:18][N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN.C1COCC1>CN(C=O)C.O>[C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([NH:19][CH3:18])=[O:16])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: N#Cc1c(N2CCOCC2)sc(C(=O)O)c1I
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylic acid (7.1 g, 19.4 mmol) in DMF (195 mL) were added HATU (8.9 g, 23.4 mmol) and DIPEA (4.1 mL, 23.3 mmol). The reaction mixture was allowed to stir at rt for 1 h and a 2.0 M solution of methylamine in THF (19.4 mL, 38.8 mmol) was added. The reaction mixture was allowed to stir at rt for 30 min and water was added. A precipitate formed and was filtered and dried to give 4-cyano-3-iodo-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (6.4 g, 87%). LCMS: (FA) ES+ 378.0, ES− 376.1. 1H NMR (400 MHz, d6-DMSO) δ: 7.92 (m, 1H), 3.72-3.76 (m, 4H), 3.47-3.51 (m, 4H) and 2.73 (d, 3H).
Reaction SMILES: I[C:2]1[CH:20]=[CH:19][C:5]2[O:6][CH2:7][C:8]([F:18])([CH3:17])[C:9]3[N:10]([N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=3)[C:4]=2[CH:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[CH:23]=1>>[F:18][C:8]1([CH3:17])[CH2:7][O:6][C:5]2[CH:19]=[CH:20][C:2]([C:30]#[C:29][C@@:27]([OH:31])([C:24]3[CH:23]=[C:22]([CH3:21])[O:26][N:25]=3)[CH3:28])=[CH:3][C:4]=2[N:10]2[N:11]=[C:12]([C:14]([NH2:16])=[O:15])[CH:13]=[C:9]12
Reactant: CC1(F)COc2ccc(I)cc2-n2nc(C(N)=O)cc21
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-n2nc(C(N)=O)cc2C(C)(F)CO3)no1

Procedure:
Similar to as described in General Procedure G, racemic 9-iodo-4-fluoro-4-methyl-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol to give a diasteromeric mixture of the titled compound after purification by prep HPLC.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][N:7]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:20][C@@H:16]2[CH2:17][CH2:18][CH2:19][N:15]2[C:10]([C:9]2[CH:8]=[N:7][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C(O)c1ccc(-c2cccs2)nc1
Product: O=C(c1ccc(-c2cccs2)nc1)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D using 6-thiophen-2-yl-nicotinic acid (CAS 179408-54-9) and (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine to give the title compound (58 mg). MS (ES+) 342.1 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][OH:15])=[CH:4][CH:3]=1.[CH3:16][C@H:17]([N:24]=[C:25]=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][O:15][C:25](=[O:26])[NH:24][C@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CO
Product: Cc1noc(-c2ccc(Br)cc2)c1COC(=O)N[C@@H](C)c1ccccc1

Procedure:
Prepared according to the procedure described in Example 19, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-methanol and (S)-(−)-α-methylbenzyl isocyanate.
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[N+:20]([O-])=O.O=[Si]=O>C(O)C.[Ru]>[CH3:4][O:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[NH2:20]
Reactant: COc1cc(Br)ccc1-c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Ru]
Agent: NN
Agent: O=[Si]=O
Solvent: CCO
Solvent: O
Product: COc1cc(Br)ccc1-c1ccc(Br)cc1N
Temperature: 67.5 °C
Yield: 95.4 %

Procedure:
A solution of hydrazine hydrate (19.4 mL, 400 mmol) in ethanol (20 mL) was added dropwise into a suspension of 2-methoxy-2′-nitro-4,4′-dibromobiphenyl (15, 25.77 g, 66.59 mmol) and 5% Ru/C (2.69 g, 1.33 mmol) in ethanol (250 mL) maintained at 65-70° C. The reaction mixture was then refluxed for 7 h. The hot reaction mixture was passed through Celite 545 (1 cm thick), and the filtrate was evaporated to give an off-white powder (22.69 g, 95.46%): mp 94.5-97° C.; HPLC method 3 tR=18.57 min (97.9 area %); 1H NMR δ 3.40 (br s, 2 H), 3.80 (s, 3 H), 6.9-7.2 (m, 6 H); EI-MS m/z 355 (M+). Anal. (C13H11ONBr2) C, H, N.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3nc(-c4ccccc4)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3nc(-c4ccccc4)cs3)cnc(CN)c2cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 71 %

Procedure:
[6,7-Dimethoxy-4-(4-phenyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester (44 mg, 0.0853 mmol) in CH2Cl2 (1 mL) was added a 4.0 M HCl solution in dioxane (0.21 mL) at room temp. After the reaction mixture was stirred at room temperature for 21 h, the suspension was filtered. The yellow solid was further dried in vacuo to give (1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-(4-phenyl-thiazol-2-yl)amine hydrochloride salt (26.1 mg; 71%). 1H-NMR (D2O): δ, 8.82 (s, 1H), 7.09-7.00 (m, 6H), 6.69 (s, 1H), 6.51 (s, 1H), 4.43 (s, 2H), 3.70 (s, 3H), 3.59 (s, 3H); MS: calculated for C21H21N4O2S (M−Cl) 393.0; found: 393.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH:20][C:27](=[O:30])[CH2:28][CH3:29])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) (150 mg, 0.56 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL), cooled at 0° C., propionyl chloride (57 mg, 0.62 mmol) was added dropwise. Upon complete addition, the ice bath was removed and the reaction continued at room temperature overnight. Then CH2Cl2 (10 mL) and aqueous NaOH 10% (10 mL) were added, the organic layer was separated, and washed with H2O and saturated NaCl. The combined organic layers were dried over Na2SO4, filtered and concentrated in vaccuo. The crude product was purified by column chromatography on silica gel, eluting with an EtOAc/hexane gradient (80-100%), yielding the target product (100 mg, 55%)
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=[O:9])=[O:5].[CH3:24][O:25][C:26]1[N:31]=[C:30]([O:32][CH3:33])[C:29]([CH:34]=O)=[CH:28][N:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[NH2:1][C:2]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][C:8]([NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([CH2:34][C:29]2[C:30]([O:32][CH3:33])=[N:31][C:26]([O:25][CH3:24])=[N:27][CH:28]=2)[CH2:12]1)=[O:9])=[O:5]
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)NCC(=O)N[C@@H]1CCNC1
Reactant: COc1ncc(C=O)c(OC)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ncc(CN2CC[C@@H](NC(=O)CNC(=O)c3cc(C(F)(F)F)ccc3N)C2)c(OC)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-3-[{N-(2-Amino-5-trifluoromethylbenzoyl)glycyl}amino]pyrrolidine (17.2 mg, 0.04 mmol) was dissolved in THF (1 mL) and 2,4-dimethoxy-5-pyrimidine carboxaldehyde (6.7 mg, 0.04 mmol) was added followed by sodium triacetoxyborohydride (12.7 mg, 0.06 mmol) and glacial acetic acid (2.4 mg, 0.04 mmol). The mixture was stirred at room temperature for 24 h and evaporated. The residue was then dissolved in dichloromethane (1 mL) and washed with 1 N NaOH solution (1 mL). The organic phase was recovered and evaporated then treated with 25% trifluoroacetic acid in dichloromethane (1 mL) for 1 h at room temperature and evaporated. The residue was purified using LC/MS to afford (R)-3-[{N-(2-amino-5-trifluoromethylbenzoyl)glycyl}amino]-1-(2,4-dimethoxypyrimidin-5-ylmethyl)pyrrolidine (Compound No. 2175) (18.6 mg, 78%): The purity was determined by RPLC/MS (98%); ESI/MS m/e 483 (M++H, C21H25F3N6O4).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:11]C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1>N1C=CC=CC=1>[C:4]1([S:7]([NH2:11])(=[O:9])=[O:8])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)C(=O)c1ccccc1C2=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1.32 mol (166 cm3) of benzenesulfochloride is added little by little at 45° C. with constant stirring to a solution of 1 mol (223 g) of 2-amino anthraquinone in 1800 cm3 of pyridine. When the addition is complete the reaction mixture is kept at 45° C. for 4 hours. It is then cooled to 0° C. Drying yields the crude product which is then washed successively in slightly hydrochloric water, in water, and in alcohol. 320 g of practically pure benzene-sulfonamide are thus obtained, which melt at 276° C. 12 g of slightly less pure benzene-sulfonamide may be recovered from the pyridine filtrate by dilution.
Reaction SMILES: C1O[C:5](O)([CH2:7]O)[CH2:4][O:3][C:2]1([OH:12])[CH2:10][OH:11].[CH2:13](O)CCO>>[C:10]([CH:2]1[O:3][CH2:4][CH2:5][CH2:7][O:12]1)(=[O:11])[CH3:13]
Reactant: OCCCO
Reactant: OCC1(O)COC(O)(CO)CO1
Product: CC(=O)C1OCCCO1
Temperature: 105 °C
Reaction time: 4 h
Yield: 53 %

Procedure:
A mixture of 3.81 g of 1,3-dihydroxyacetone dimer (available from Aldrich Chemical Co., Milwaukee, Wis.) and 308 mg of Amberlyst-15 ion-exchange resin (Aldrich Chemical Co., Milwaukee, Wis.) in 10 mL of 1,3-propanediol was stirred for four hours at a temperature of about 105° C. (external oil bath temperature) and protected from atmospheric moisture. After cooling the mixture to room temperature, it was filtered through a plug of glass wool into a separatory funnel containing 50 mL of 10% aqueous sodium chloride; and the product was isolated by extraction with dichloromethane (2×15 mL portions). The combined dichloromethane extracts were washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate and filtered. Removal of dichloromethane by evaporation at reduced pressure, followed by evaporative distillation (bath temperature: 72°-91° C., 2.5 mm) afforded 2.92 g (53% yield) of the desired product, greater than 98% pure as shown by gas chromatographic analysis. The title compound, 2-acetyl-1,3-dioxane, has been previously prepared in a similar manner by S. K. Gupta, J. Org. Chem., 41, 2642 (1976).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[NH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][C:31]([O:35][C:36]([F:39])([F:38])[F:37])=[CH:30][CH:29]=3)[O:24][CH:25]=1>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[N:22]=[C:23]([C:26]4[NH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][C:31]([O:35][C:36]([F:39])([F:37])[F:38])=[CH:30][CH:29]=5)[O:24][CH:25]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc2[nH]c(-c3nc(COc4ccc(CCCCn5ccnn5)cc4)co3)cc2c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (7 mg, 0.28 mmol) was given at 0° C. to a solution of 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol (55 mg, 0.25 mmol) in 2.0 ml N,N-dimethyl formamide and stirred for 30 min. 2-(4-Chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole (80 mg, 0.25 mmol) dissolved in 1.0 ml N,N-dimethyl formamide was added at 0° C. and stirring continued at 0° C. for 1 h and 12 h at room temperature thereafter. The mixture was quenched with water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with brine (10 ml), dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate) yielded 2-{4-[4-(4-[1,2,3]Triazol-1-yl-butyl)-phenoxymethyl]-oxazol-2-yl}-5-trifluoromethoxy-1H-indole as off white solid. Yield 50 mg (40%)
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.OC1[C:27]2[N:26]=NN[C:23]=2[CH:22]=[CH:21]C=1.C(N(CC)CC)C.C1(CN)CC1>C(Cl)Cl>[CH:23]1([CH2:27][NH:26][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:6])[CH2:21][CH2:22]1
Reactant: O=C(O)C1CC1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: NCC1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Cyclopropyl carboxylic acid (1.0 g, 11.63 mmol) was added to a 50 mL two neck round bottom flask, along with DCM (25 mL). This mixture was cooled to 0° C., EDCI (4.15 g, 13.95 mmol) was added portionwise to the mixture with stirring under nitrogen atmosphere, and the temperature was maintained for 0.5 h. After this time, hydroxybenzotriazole (1.88 g, 13.95 mmol) was added to the 0° C. mixture which was stirred for 10 min, then triethylamine (1.7 g, 11.63 mmol) was added, and stirring of the mixture was continued at the same temperature for another 0.5 h. Then, cyclopropylmethylamine (0.825 g, 11.63 mmol) was added, and the reaction was allowed to reach RT, and stirring was continued overnight. The solvent was then removed in vacuo, and the crude residue was purified by passing through a column over 60-120 silica gel, eluting with dichloromethane, to afford the title compound (1.6 g), yield: 87%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]2[O:1][C:2]3[C:3](=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[CH:10][CH:11]=3)[N:12]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1cccc(O)c1N
Product: COC(=O)c1cccc2oc(-c3ccc(OC)cc3)nc12
Yield: 18 %

Procedure:
Methyl 2-(4-methoxyphenyl)benzoxazole-4-carboxylate was prepared from methyl 3-hydroxyanthranilate and 4-methoxybenzoyl chloride as described in Step A of Example 1. The product was obtained as an off-white solid in 18% yield. δ 8.29 (m, 2H), 8.01 (dd, J=7.8, 1.0 Hz, 1H), 7.74 (dd, J=8.1, 1.0 Hz, 1H), 7.37 (t, J=7.9 Hz, 1H), 7.03 (m, 2H), 4.06 (s, 3H); 3.91 (s, 3H); MS (ESI) m/z 284 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[C:17]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:16][C:7]2=[N:8][C:9]=1[N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])(=[O:3])[CH3:2].[BH4-]>O1CCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:17]2[O:16][C:7]3=[N:8][C:9]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:12])=[O:13])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=[C:6]3[C:18]=2[C:19]([NH:21][CH3:22])=[O:20])=[CH:24][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(C(C)=O)cc12
Agent: [BH4-]
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(C(C)O)cc12
Yield: 49.8 %

Procedure:
To 5-acetyl-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridine-3-carboxamide (3 mg, 7.15 μmol) in tetrahydrofuran (0.1 ml) was added 10 mg of resin-bound borohydride (Aldrich cat#328642, 2.5 mmol BH4/g). After LCMS indicated complete conversion to product, the reaction mixture was filtered and purified by HPLC to afford the title compound (1.5 mg, 50%). MS (ESI) m/z 422.3 (M+1). NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.03-7.99 (m, 2H), 7.26-7.22 (m, 2H), 5.88 (br s, 1H), 5.55-5.53 (m, 1H), 3.37 (s, 3H), 3.13 (s, 3H), 3.06-3.05 (d, 3H), 1.61-1.60 (d, 3H)