Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[Na].BrC1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][C:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[C:15]2[CH:22]=[O:23].ClCCl>CN1CCCC1=O.O.[Cu]I>[CH3:21][O:20][C:19]1[C:3]([C:2]([F:7])([F:6])[F:1])=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([CH:22]=[O:23])=[C:14]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:13]=[CH:12]2
Reactant: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1Br
Reactant: O=C(O)C(F)(F)F
Agent: [Cu]I
Agent: [Na]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc2c(C=O)c(OCc3ccccc3)ccc2c1C(F)(F)F
Temperature: 180 °C
Yield: 58 %

Procedure:
A suspension of copper (I) iodide (35.5 g, 0.186 mol), trifluoroacetic acid, sodium salt (50 g, 0.37 mol), and 5-bromo-6-methoxy-2-(phenylmethoxy)-1-naphthalenecarboxaldehyde (17.3 g, 0.047 mol, described in Example 6) in anhydrous 1-methyl-2-pyrrolidinone (150 mL) was stirred vigorously and heated at 180° C. under argon for 1.5 hours, then cooled. The mixture was then suspended in 1 L of water and 1 L of ether and filtered through Solka-Floc*. The filtrate was separated into two phases and the ether layer was washed with water (3X) and then washed with saturated NaCl and dried over Na2SO4. The Solka-Floc filter cake was then washed thoroughly with dichloromethane and the filtrate was washed with water (3X), and then with brine and dried over Na2SO4. After filtration and concentration, the residues from the ether and dichloromethane solutions were combined, dissolved in dichloromethane (250 mL) and filtered through silica gel with additional dichloromethane. The filtrate was concentrated and chromatographed on silica gel with 1:1 hexane:dichloromethane to give 9.8 g (58% yield) of the title compound of suitable purity for subsequent reaction, m.p. 143°-145° C. (from ethanol).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C:6]2[CH:8]=[C:9]3[O:14][CH2:13][O:12][C:10]3=[CH:11][C:5]=2[CH:4]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[O:3]1.CS(C)=[O:26].[OH-].[Na+].Cl>CN(C)C=O>[CH3:1][C@H:2]1[CH2:7][C:6]2[CH:8]=[C:9]3[O:14][CH2:13][O:12][C:10]3=[CH:11][C:5]=2[C:4]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)([OH:26])[O:3]1
Reactant: CS(C)=O
Reactant: C[C@H]1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)O1)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: C[C@H]1Cc2cc3c(cc2C(O)(c2ccc([N+](=O)[O-])cc2)O1)OCO3
Reaction time: 4.5 h

Procedure:
350 grams of the isomeric intermediate from Example 4 was added to a solution of 731 mL of dimethylsulfoxide and 2923 mL of dimethylformamide. The mixture was cooled to 8°-12° C. and compressed air was passed through the mixture. 117.5 mL of 50% aqueous sodium hydroxide was added in one portion and the resulting mixture was stirred for 4.5 h. The reaction mixture was added by cannula over 30-60 min to 8.25 L of a stirred 1N hydrochloric acid solution at 10°-15° C. The resulting precipitate was filtered and washed with 3 L of water then air dried to a constant weight (384 g). The wet cake was carried into Example 6 without further drying. P chem: Data recorded from a 3:1 isomeric mixture. TLC Rf =0.19 (75:25 hexane:ethyl acetate); IR (CHCl3) 3605, 3590, 3015, 3000, 2960, 2910, 1608, 1522, 1484, 1352, 1240, 1042cm-1 ; HNMR (CDCl3, 300 MHz) δ (major isomer) 8.16 (d, 2H, J=6.9 Hz), 7.73 (d, 2H, J=6.9 Hz), 6.55 (s, 1H), 6.38 (s, 1H), 5.86 (s, 1H), 5.83 (s, 1H), 4.38 (M, 1H), 2.70 (m, 2H), 1.39 (d, 3H, J=6.3 Hz); d (minor isomer) 8.27 (d, 2H, J=8.9 Hz), 7.90 (d, 2H, J=8.6 Hz), 6.87 (s, 1H), 6.73 (s, 1H), 6.03 (s, 1H), 6.02 (S, 1H), 3.95 (m, 1H), 2.7 (obscured, m, 2H), 1.24 (d, 3H, J=6.1 Hz); mass spectrum, m/z (FD, M+) 329; Anal. Calcd. for C17H15NO6 : C, 62.01; H, 4.59; N, 4.25. found C, 62.22, H, 4.79; N, 4.29.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15].COCCOC.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O.C(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:31]3[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:33][C:32]=3[O:34][CH3:35])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: CCCNC(=O)c1nnc2c(I)c(F)ccc2c1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: CCCNC(=O)c1nnc2c(-c3ccc(OC)cc3OC)c(F)ccc2c1N
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 63.5 %

Procedure:
A 2 L, 3-necked flask equipped with a mechanical stirrer was charged with 4-amino7-fluoro-8-iodo-N-propylcinnoline-3-carboxamide (40.5 g, 108.2 mmol), DME (700 mL, anhydrous), and ethanol (200 mL, absolute). A nitrogen dispersion tube was fitted into the suspension and the mixture was stirred until a solution was obtained. Water (300 mL) and PdCl2(PPh3)2 (7.6 g, 10mol %) were added. After 5 minutes, 2,4-dimethoxyphenyl boronic acid (39.4 g, 216.5 mmol) was added followed by cesium carbonate (70.3 g, 216.5 mmol). Nitrogen was bubbled through the suspension for 5 minutes. The mixture was heated to approximately 80° C. Additional 7:3:2 DME:H2O:EtOH (340 mL) was added as the reflux started. The reaction was refluxed 18 hours and then cooled to room temperature, diluted with ethyl acetate (1.5 L), and washed with water (3×500 mL). The aqueous layers were extracted with ethyl acetate (3×150 mL). The combined organic layers were stirred for 1 hour with 40 g of DARCO, dried over sodium sulfate, and filtered through Celite. The solids were washed with 5% methanol in chloroform (3×200 mL) and the filtrates concentrated to a dark semisolid. This was taken up in 200 mL 1% methanol in chloroform and warmed to solubilize the material. The solution was divided into two portions. Each portion was filtered through Whatman fluted filter paper onto a 330 g silica gel column and eluted with 5% ethyl acetate in dichloromethane. (Note: Some solid catalyst appeared to be removed via the filter paper.) The purest fractions from each column were combined in 5-10% ethyl acetate in dichloromethane. The solution was concentrated to approximately 200 mL, diluted with hexane (200 mL), and let stand at room temperature overnight. The resulting solids were isolated by filtration, washed with ether (3 times), and dried under vacuum at room temperature to afford the desired product (26.4 g, 63%). 1H NMR (500.333 MHz, CDCl3) δ 8.51 (bs, 1H), 7.86 (dd, J=9.4, 5.2 Hz, 1H), 7.50 (t, J=8.8 Hz, 1H), 7.27 (d, J=9.2, 1H), 6.66 (dd, J=8.2, 2.3 Hz, 1H), 6.63 (d, J=2.3 Hz, 1H), 3.87 (s, 3H), 3.71 (s, 3H), 3.44 (q, J=6.7 Hz, 2H), 1.64 (sextet, J=7.3 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H). MS APCI, m/z=385 (M+H). HPLC 2.61 min.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:29])[NH:22][CH2:23][C@@H:24]1[CH2:26][C@H:25]1[CH:27]=O)([CH3:19])([CH3:18])[CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:16]([O:20][C:21](=[O:29])[NH:22][CH2:23][C@@H:24]1[CH2:26][C@H:25]1[CH2:27][N:11]1[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=2)[CH2:9][CH2:10]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1C=O
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H]1CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (0.300 g, 1.2 mmol), Trans-(2-Formyl-cyclopropylmethyl)-carbamic acid tert-butyl ester (0.294 g, 1.2 mmol), in 1, 2 dichloroethane (2 mL) was stirred for 4 h at room temperature and sodium triacetoxyborohydride (0.470 g, 2.2 mmol) was added and the resulting solution was stirred for 12 hours until the TLC indicated completion of the reaction. The mixture was filtrated and concentrated to dryness and purified with column chromatography on silica gel using CH2Cl2—CH2Cl2/MeOH (1-9:1). The product fractions were concentrated to give 0.288 g (0.74 mmol, 60% yield) of a white solid. MS (m/e): 391.3 (M+H+).
Reaction SMILES: Cl.[NH2:2][C@@:3]([CH3:18])([CH2:15][CH2:16][CH3:17])[C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:5].[F:19][C:20]([F:42])([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:21][C@H:22]([NH:26][C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28])[C:23](O)=[O:24].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[C:4]([C@:3]([NH:2][C:23]([C@@H:22]([NH:26][C:27]([N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)=[O:28])[CH2:21][C:20]([F:42])([F:19])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:24])([CH3:18])[CH2:15][CH2:16][CH3:17])=[O:5]
Reactant: CCC[C@](C)(N)C(=O)c1nc2ccccc2o1
Reactant: O=C(O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@](C)(NC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of (S)-2-amino-1-benzoxazol-2-yl-2-methyl-pentan-1-one hydrochloride (80.6 mg, 0.3 mmol), (S)-4,4-difluoro-2-[(morpholine-4-carbonyl)-amino]-5-phenyl-pentanoic acid (0.102 mg, 0.3 mmol), EDCI (69 mg, 0.36 mmol), HOBT (48.6 mg, 0.36 mmol) and Diisopropyl ethylamine (0.2 mL) in DMF is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed with cold 1N HCl, saturated NaHCO3 and then saturated NaCl solution. The organic phase is dried over magnesium sulfate and solvent evaporated under reduced pressure to give the crude product. Purification by Silica gel column chromatography, eluting with ethyl acetate and heptane mixture gives morpholine-4-carboxylic acid {(S)-1-[(S)-1-(benzoxazole-2-carbonyl)-1-methyl-butylcarbamoyl]-3,3-difluoro-4-phenyl-butyl}-amide (82%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([I:12])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:21][CH3:22].CCOC(C)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][CH3:22])=[C:7]([I:12])[CH:6]=1)[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)c1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(OCC)c(I)c1

Procedure:
To the resultant ester (3.10 g, 10.61 mmol) and potassium carbonate (2.87 g, 20.75 mmol) in 40 ml acetonitrile, add iodoethane (1.3 ml, 16.25 mmol) at RT while stirring vigorously. Heat the resulting white suspension under reflux for 1.5 h. Evaporate acetonitrile and replace with EtOAc. Wash the organic layer first with water, then with saturated aq. sodium chloride. Dry over anhydrous sodium sulfate, filter and concentrate to give the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1.[N:31]1([CH2:37][CH2:38]Cl)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Br:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([O:14][CH2:38][CH2:37][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[C:15]1[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc(-c2nc3ccc(O)cc3n2Cc2ccccc2Br)cc(OC)c1OC
Product: COc1cc(-c2nc3ccc(OCCN4CCCCC4)cc3n2Cc2ccccc2Br)cc(OC)c1OC

Procedure:
The title compound was prepared by reacting the compound of Example 114 with 2-(piperidin-1-yl)ethyl chloride essentially as previously described. mp 145° C., NMR, MS 579, 581, IR.
Reaction SMILES: [NH:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>CN(C=O)C>[C:19]([CH2:18][N:1]1[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11])#[N:20]
Reactant: CCOC(=O)c1cc2c([nH]1)CCCC2
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(n1CC#N)CCCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A 125-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with 101h (5.76 g, 29.8 mmol) and DMF (50 mL). The solution was cooled to 0° C. using an ice bath. NaH (60% dispersion in mineral oil, 1.43 g, 35.8 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. After that time, bromoacetonitrile (1.43 g, 35.8 mmol) was added. The mixture was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 mL) and water (450 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 55% yield (3.80 g) of ethyl 1-(cyanomethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate 101i as a yellow semi-solid: 1H NMR (300 MHz, CDCl3) d 6.66 (s, 1H), 5.29 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 2.62 (t, 2H, J=6.3 Hz), 2.49 (t, 2H, J=6.3 Hz), 1.92 (m, 2H), 1.75 (m, 2H), 1.33 (t, 3H, J=7.2 Hz); MS (ESI+) m/z 233.1 (M+H)
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:29].CCOCC>O1CCOCC1>[ClH:29].[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)=[CH:16][CH:17]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(Br)cc2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Brc1ccc(Cc2ccc(OC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 20 mL vial which contained a solution the product from step 4 (130 mg, 0.3 mmol) in dioxane was added HCl (4 N in dioxane, 2 mL) at 0° C. The mixture was allowed to warm to rt and stirred at rt for 16 h. The solvent was reduced to 1 mL and ether (15 mL) was added to this vial. the resulting solid was filtered out and dried in vacuo to yield the title product as a hydrogen chloride salt (80 mg, 80%); LCMS; 99%, ESI+, (Calcd: 346.3; Found m/z: 347.6, (M+1), 348.1, (M+2); 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.07-2.14 (m, 1H), 3.15-3.24 (m, 2H), 3.86 (s, 2H), 3.83-3.92 (m, 1H), 4.02-4.07 (m, 1H), 4.21 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.15-7.18 (m, 4H), 7.46 (d, J=8.4 Hz, 2H):
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1cc(Cl)c(C#N)c(Cl)c1
Product: Cc1cc(Cl)c(C(N)=O)c(Cl)c1
Temperature: 0 °C
Yield: 59 %

Procedure:
To stirred, cooled concentrated sulfuric acid (40 ml) was added in portions 2,6-dichloro-4-methylbenzonitrile (13.2 g, 71.0 mmol). The mixture was heated on a steam bath for 3 hours with occasional shaking, cooled, poured into ice-water, and extracted twice with dichloromethane. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (390 g) eluted with 4:1 (v/v) dichloromethane-diethyl ether to provide 8.6 g (59%) of 2,6-dichloro-4-methylbenzamide, m.p. 101°-107° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[C:15]2[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[N:13][CH:12]=[N:11][C:10]=2[S:9][C:8]=1[CH3:27]>>[N:1]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:15]3[CH:7]=[C:8]([CH3:27])[S:9][C:10]=3[N:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: Cc1sc2ncnc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 5-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([C:20]3[N:21]=[N:22][NH:23][N:24]=3)[CH:17]=[CH:16][N:15]=2)[N:11]=[CH:10]1.[C:25]([O:28][CH2:29]Cl)(=[O:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:25]([O:28][CH2:29][N:22]1[N:23]=[N:24][C:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([C:12]3[N:11]=[CH:10][N:9]([CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:13]=3)[CH:19]=2)=[N:21]1)(=[O:27])[CH3:26]
Reactant: Clc1ccccc1Cn1cnc(-c2cc(-c3nn[nH]n3)ccn2)c1
Reactant: CC(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCn1nnc(-c2ccnc(-c3cn(Cc4ccccc4Cl)cn3)c2)n1
Yield: 15 %

Procedure:
The title compound was prepared in 15% yield from 2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(2H-tetrazol-5-yl)pyridine (Example 129), chloromethyl acetate and potassium carbonate in DMF. 1H NMR (400 MHz, DMSO): δ 2.12 (3H, s), 5.41 (2H, s), 6.67 (2H, s), 7.27-7.29 (1H, m), 7.38-7.41 (2H, m), 7.53-7.55 (1H, m), 7.81 (1H, s), 7.94 (1H, s), 8.51 (1H, s), 8.68 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H16ClN7O2, 410. Found, 410.
Reaction SMILES: Cl[C:2]1C=CC(OC2C=CC(NCC(N[C@@H](CC3C=CC=CC=3)C(NCCN3CCCC3)=O)=O)=CC=2)=CC=1.[Cl:38][C:39]1[CH:75]=[CH:74][C:42]([O:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]=[C:51]([NH:71][C:72]#[N:73])[NH:52][CH:53]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH2:54][C:55]([NH:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:56])=[CH:46][CH:45]=2)=[CH:41][CH:40]=1>>[Cl:38][C:39]1[CH:40]=[CH:41][C:42]([O:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]=[C:51]([NH:71][C:72]#[N:73])[NH:52][C@@H:53]([CH2:65][C:66]3[CH:2]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:54][C:55]([NH:57][CH2:58][CH2:59][N:60]3[CH2:64][CH2:63][CH2:62][CH2:61]3)=[O:56])=[CH:46][CH:45]=2)=[CH:74][CH:75]=1
Reactant: N#CNC(=Nc1ccc(Oc2ccc(Cl)cc2)cc1)NC(CC(=O)NCCN1CCCC1)c1ccccc1
Reactant: O=C(CNc1ccc(Oc2ccc(Cl)cc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCN1CCCC1
Product: N#CNC(=Nc1ccc(Oc2ccc(Cl)cc2)cc1)N[C@H](CC(=O)NCCN1CCCC1)Cc1ccccc1

Procedure:
Prepared as in Example 8 from [(S)-1-benzyl-2-(2-pyrrolidin-1-yl-ethylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 27, step A) and 1-[4-(4-chloro-phenoxy)-phenyl]-3-cyano-thiourea (Example 32, step A). MS (electrospray): mass calculated for C30H33ClN6O2, 544.24; m/z found, 545.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.27–7.08 (m, 9H), 6.91 (t, J=9.4 Hz, 4H), 6.25 (br s, 1H), 4.35–4.26 (m, 1H), 3.35–3.28 (m, 1H), 3.25–3.17 (m, 1H), 2.99 (dd, J=13.5, 6.4 Hz, 1H), 2.7–2.68 (m, 1H), 2.52 (t, J=5.9 Hz, 2H), 2.49–2.41 (m, 4H), 2.41–2.35 (m, 1H), 2.26–2.18 (m, 1H), 1.74–1.69 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[CH:16]([CH2:17][CH:18]([O:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C(Cl)(Cl)Cl.CCO.Cl>C1(C)C=CC=CC=1.O.[Pt]=O>[NH2:32][CH2:31][CH2:30][CH2:29][O:28][CH:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCCC#N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Pt]
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4CC(OCCCN)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-(Cholestan-3-yloxy)propanenitrile 135 (442 mg, 1 mmol) was taken up in a mixture of toluene (1 mL), chloroform (1.5 mL), EtOH (1 mL) and conc. HCl (200 μL). Platinum oxide hydrate (46 mg) was added. The mixture was stirred under hydrogen (80 psi) at room temperature for 48 hours. The solvent was evaporated and the residue taken up with DCM (40 mL) and NaHCO3 (sat.) (40 mL). The organic phase was separated and washed with NaHCO3 (sat.) (30 mL), followed by brine (20 mL), before being dried (Na2SO4) and the solvent evaporated to yield the white foam product which was reacted on without further purification or characterization.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]2[N:6]([C:10]([CH:29]3[CH2:32][C:31](=[O:33])[CH2:30]3)=[N:11][C:12]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][N:9]=1>>[Cl:3][C:4]1[C:5]2[N:6]([C:10]([C@@H:29]3[CH2:30][C@H:31]([OH:33])[CH2:32]3)=[N:11][C:12]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Product: O[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ethanolic suspension (20 mL) of 3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanone: (2.5 mmol) was charged with NaBH4(2.5 mmol) at rt. The reaction mixture was stirred at rt for 30 min until the reaction solution turned clear. The reaction mixture was quenched by an addition of Na2SO4.10H2O and concentrated under reduced pressure. The crude mixture was dissolved in DCM, washed with water (3×15 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.93-7.87 (m, 3H), 7.58-7.52 (m, 3H), 7.47-7.45 (m, 1H), 7.37 (d, J=5.2 Hz, 1H), 4.44 (b, 1H), 3.37 (p, J=8.0 Hz, 1H), 3.03-2.96 (m, 2H), 2.60-2.53 (m, 2H); MS (ES+): m/z 427 (100) [MH+].
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[CH2:10]([O:17][C:18]1[C:19]([CH:36]=[O:37])=[N:20][CH:21]=[C:22]([C:34]=1[OH:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:38]>O1CCCC1>[CH2:10]([O:17][C:18]1[C:19]([C:36]([OH:38])=[O:37])=[N:20][CH:21]=[C:22]([C:23](=[O:24])[NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:34]=1[OH:35])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O
Reactant: O=Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)O)c(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an aqueous solution (105 ml) of sodium chlorite (7.13 g, 78.8 mmol), and sulfamic acid (7.65 g, 78.8 mmol) was added a solution of the compound 12 (15.0 g, 39.4 mmol) in tetrahydrofuran (630 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After water (2500 ml) was added to the reaction solution, precipitated crystals were filtered. Washing with diethyl ether afforded 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid 13 (14.0 g, 90%) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH3:10])=[N:4][CH:3]=1.[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[C:13]([CH3:22])=[C:14]([S:18]([NH:8][C:6]2[C:5]([O:9][CH3:10])=[N:4][CH:3]=[C:2]([Cl:1])[N:7]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: COc1ncc(Cl)nc1N
Product: COc1ncc(Cl)nc1NS(=O)(=O)c1cccc(Cl)c1C

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 6-chloro-3-methoxy-2-pyrazinamine (0.16 g) and 3-chloro-2-methylbenzenesulphonyl chloride (0.23 g). Yield 0.15 g.