Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[CH2:5]([S:19][CH2:20][CH:21]1[O:23][CH2:22]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][CH2:22][CH:21]([OH:23])[CH2:20][S:19][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: NCCO
Reactant: CCCCCCCCCCCCCCSCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCCCSCC(O)CNCCO
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A 300-ml flask equipped with a stirrer and dropping funnel was charged with 61.1 g (1 mol) of ethanolamine and 61 g of ethanol. While stirring the contents at 80° C., a solution of 14.3 g (50 mmol) of 1-tetradecylthio-2,3-epoxypropane in 30 g ethanol was added dropwise over 3 hours. After completion of the dropping, the resultant reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from hexane, thereby obtaining 15.8 g (yield: 91%) of the title compound (IIe-1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].[C:20]([Cu])#[N:21].[C-]#N.[Na+]>CN(C=O)C>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:20]#[N:21])[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Yield: 48.3 %

Procedure:
A mixture of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A; 0.50 g, 1.3 mmol) and CuCN (0.14 g, 1.6 mmol) was refluxed for 90 minutes in DMF (5 mL). The residue was poured into 25% aq. NaCN (30 mL), extracted with CHCl3, dried over MgSO4, and concentrated. The crude was purified by silica gel flash column chromatography (0.5% MeOH in CH2Cl2) to afford 0.179 g (49%) of the desired product. LRMS (APCI pos) m/e 286.2 (M+1). 1H-NMR (400 MHz, CDCl3) δ 8.62 (d, 1H), 8.08 (s, 1H), 7.05 (t, 1H), 6.67 (d, 1H), 6.53 (m, 2H), 3.87 (s, 2H); 19F-NMR (376 MHz, CDCl3) δ −128.4.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1.[CH2:15]([CH:18]([C:21]#[N:22])[C:19]#[N:20])[CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:15]([C:18]([CH2:2][N:3]1[CH:7]=[N:6][C:5]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])=[N:4]1)([C:21]#[N:22])[C:19]#[N:20])[CH:16]=[CH2:17]
Reactant: C=CCC(C#N)C#N
Reactant: FC(F)(F)C(F)(F)c1ncn(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCC(C#N)(C#N)Cn1cnc(C(F)(F)C(F)(F)F)n1

Procedure:
1-(chloromethyl)-3-(pentafluoroethyl)-1H-1,2,4-triazole and 1.02 g of allyl malononitrile were dissolved in 28 ml of N,N-dimethylformamide. 2.76 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and then subjected to preparative high performance liquid chromatography to obtain 0.54 g of allyl {[3-(pentafluoroethyl)-1H-1,2,4-triazole 1-yl]methyl}malononitrile (referred as the compound of the present invention (35), hereinafter) shown by below formula.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][Cl:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccnc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cccnc1Cl

Procedure:
To the solution of 2-choronicotinic acid (5 g, 31.84 mmol) in dry DCM under nitrogen, Oxalyl chloride (38.21 mmol) and catalytic amount of N,N-dimethylformamide were added carefully with stirring. The reaction was stirred for 3 hr. The solution was concentrated under vacuum to yield 2-chloronicotinyl chloride as solid which was used for next reaction without purification.
Reaction SMILES: [NH4+].[Cl-].[CH3:3][C:4]1([CH3:20])[O:8][C@H:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH2:6][O:5]1.C(O)(C)C>[Fe].O>[CH3:3][C:4]1([CH3:20])[O:8][C@H:7]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[NH2:17])[CH2:6][O:5]1
Reactant: CC1(C)OC[C@@H](COc2cccc([N+](=O)[O-])c2)O1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC1(C)OC[C@@H](COc2cccc(N)c2)O1
Yield: 75.8 %

Procedure:
Under nitrogen, Fe powder (2.38 g, 42.54 mmol) and NH4Cl (2.38 g, 42.54 mmol) were combined, followed by addition of (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane (132; 1.8 g, 7.09 mmol) and a 4:1 mixture of isopropanol:water (30 mL:10 mL). The reaction mixture was stirred under reflux for 18 h. The crude material was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The resulting aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to afford (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)aniline 133 (1.2 g, 79% yield). The material was used in the next step without any further purification.
Reaction SMILES: Cl[Si:2]([CH2:10][Cl:11])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.N1C=CN=C1>CN(C)C=O.O>[Cl:11][CH2:10][Si:2]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)O
Reactant: C[Si](Cl)(CCl)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)O[Si](C)(CCl)c1ccccc1
Reaction time: 2 h
Yield: 76.9 %

Procedure:
A mixture of 15.4 g (0.075 mol) of chloro(chloromethyl)methyl(phenyl)silane, 14 ml (11.1 g, 0.15 mol) of t-butanol, 11.5 ml (8.3 g, 0.082 g) of triethylamine, and 0.5 g (0.008 mol) of imidazole in 60 ml of dimethylformamide was stirred at 80° for 2 hours. The resulting slurry was cooled, poured into 200 ml of water, and extracted with ether. The ether extracts were washed three times with water, followed by 0.1N aqueous HCl, saturated aqueous NaHCO3, and brine, dried over magnesium sulfate, and evaporated to leave 14.0 g of a pale orange oil. Distillation provided 11.9 g (65%) of the title compound: bp 78°-82° (0.2 mm); nD21 1.5010; ir (neat) 3080, 3060, 2990, 2940, 1600, 1435, 1395, 1370, 1260, 1245, 1195, 1125, 1060, 1030, 815, 790, 740, 725, 705, 650 cm-1 ; nmr (CDCl3): 0.5 (3H, s), 1.3 (9H, s), 2.9 (2H, s) and 7.3-7.8 (5H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11](Cl)(=[O:15])[C:12](Cl)=[O:13].[CH3:17][CH2:18][OH:19]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11](=[O:15])[C:12]([O:19][CH2:18][CH3:17])=[O:13])[NH:6]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Clc1cccc2[nH]ccc12
Reactant: CCO
Product: CCOC(=O)C(=O)c1cc2c(Cl)cccc2[nH]1

Procedure:
Intermediate compounds of Formula (IV) can be prepared by the reaction scheme depicted in FIG. 22. Acylation of 4-chloroindole (64) (oxalyl chloride, followed by an EtOH quench) provides an ethyl 4-chloroindole glyoxalate (65), which is reduced (e.g., LiAlH4) to the 4-chloroindole-3-ethanol (66). Substitution of the alcohol (66) is achieved using a suitable azide, such as Zn(N3)2, under Mitsunobu reaction conditions to provide (67). Malonate addition to (67) is accomplished as described by Kuehne J. Org. Chem., 63, 9427 (1998), to provide a malonyl enolate (68). Alkylation of the malonyl enolate (68) with a suitable alkylating agent such as NaOMe and MeI, provides (69). The azide group of (69) is reduced (sequential addition of PMe3 and H2O) to provide an aminoester (70). The aminoester (70) undergoes intramolecular cyclization, providing lactam (71) upon reflux as a solution in MeOH. Racemate (71) is separated into the enantiomers (72) and (73) by chiral support chromatography. The assignment of the absolute configurations to (72) and (73) is made by x-ray crystallographic analysis. The lactam group of each enantiomer is separately reduced (BH3) to provide amines (74) (from reduction of (72)) and (75) (from reduction of (73)), which may be formulated as the fumarate salts.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+].Br[CH2:13][CH2:14][CH2:15][Cl:16]>CS(C)=O.CCOC(C)=O>[Cl:16][CH2:15][CH2:14][CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: ClCCCn1nnc2ccccc21
Temperature: 20 °C
Reaction time: 16 h
Yield: 33.6 %

Procedure:
To a solution of benzotriazole (303 mg, 2.54 mmol) and powdered NaOH (101 mg, 2.52 mmol) in DMSO was added 1-bromo-3-chloro propane (437 mg, 2.77 mmol). The reaction mixture was stirred for 16 h at 20° C. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O (100 mL) and saturated NaCl (100 mL), dried over MgSO4 and concentrated in vacuo. Column purification (hexanes:EtOAc 4:1) yielded 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (167 mg, 34%). The title compound was prepared according to Example 286, Step C as a yellow oil (21 mg, 42%) from (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole (30 mg, 0.12 mmol) and 1-(3-chloropropyl)-1H-1,2,3-benzotriazole (48 mg, 0.24 mmol). 1H NMR (CDCl3) δ1.88-1.98 (m, 3H), 1.99-2.18 (m, 2H), 2.20-2.41 (m, 5H), 2.51-2.60 (m, 1H), 2.64-2.71 (m, 1H), 2.89-3.00 (m, 1H), 3.03-3.13 (m, 2H), 3.21-3.27 (m, 1H), 3.47-3.60 (m, 1H), 3.76-3.88 (m, 1H), 4.73 (t, 2H, J=6.6 Hz), 6.61 (t, 1H, J=7.4 Hz), 6.84 (d, 1H, J=6.6 Hz), 6.94 (dd, 1H, J=1.1, 8.1 Hz), 7.37 (td, 1H, J=1.1, 7.4 Hz), 7.49 (td, 1H, J=1.1, 7.8 Hz), 7.57 (d, 1H, J=8.0 Hz), 8.07 (d, 1H, J=8.4 Hz) ppm.
Reaction SMILES: S([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][CH:7]=1)(O)(=O)=O.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O>C1(C)C=CC=CC=1>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH3:13])[S:22]([C:19]2[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:26])[F:27])=[CH:21][CH:20]=2)(=[O:24])=[O:23])=[CH:10][CH:11]=1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(c1ccc(O)cc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
13.8 g (40 mmol) of 4-methylaminophenol hemisulfate (twice suspended in toluene and evaporated under reduced pressure to remove water) were suspended in 100 ml hexamethyldisilazane and refluxed for 2.5 h. The solution was evaporated under reduced pressure and dissolved in 270 ml THF. 9.79 g (40 mmol) of 4-(trifluoromethyl)benzenesulfonyl chloride were added slowly at 0° C. and the reaction mixture was stirred for 16 h at room temperature. 30 ml H2O were added and after 1 h the solvents were evaporated. The residue was extracted with water/Et2O (3×), the organic phases were washed with 10% NaCl, dried (Na2SO4) and evaporated to yield 13.3 g (100%) of N-(4-hydroxy-phenyl)-N-methyl-4-trifluoromethyl-benzenesulfonamide, mp: 145-146° C.; MS: 331 (M).
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[C:9]([N+:21]([O-])=O)=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(O)(=O)C.[Zn]>[CH:1]1([CH2:6][O:7][C:8]2[C:9]([NH2:21])=[N:10][CH:11]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ncc(Oc2ccccc2)cc1OCC1CCCC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ncc(Oc2ccccc2)cc1OCC1CCCC1
Temperature: 100 °C
Yield: 80 %

Procedure:
3-Cyclopentylmethoxy-2-nitro-5-phenoxy-pyridine (1.2 mmol) is dissolved in acetic acid (4 ml). After addition of water (4 ml), zinc powder (6 eq.) is added and the reaction suspension is heated to 100° C. for 90 minutes. The reaction suspension is cooled to room temperature and filtrated. The filtrate is pored into 3.5% NaOH (30 ml) and extracted with dichloromethane. The combined organic layers are extracted with brine, dried over MgSO4 and the solvent is removed in vacuo. 3-Cyclopentylmethoxy-5-phenoxy-pyridine-2-ylamine is obtained as yellow powder in a yield of 80%. HPLC (method C): 1.83 min, LC-MS (method A): 1.486 min, 285.15 (MH+).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)C.C=O.Cl.[CH3:12][NH:13][CH3:14].Cl.N.[CH2:17]([OH:19])[CH3:18]>>[CH3:12][N:13]([CH3:14])[CH2:18][C:17](=[O:19])[CH2:1][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1
Reactant: CNC
Reactant: CCO
Reactant: CC(=O)c1cccs1
Agent: C=O
Agent: Cl
Agent: N
Product: CN(C)CC(=O)Cc1cccs1

Procedure:
The synthesis of 2,5-Di-(2-thienyl)-pyrrole and N-substituted derivatives thereof is shown in FIG. 3. 3-dimethylamino-1-(2-thienyl)-propanone hydrochloride (4) is produced in 89% yield by refluxing for 16 hours a mixture of 2-acetylthiophene (1), paraformaldehyde (2), dimethylamine hydrochloride (3) and concentrated hydrochloric acid in ethanol. The product is isolated, treated with 35% aqueous ammonia and extracted with ether to yield 3-dimethylamino-1-(2-thienyl)-propanone (5).
Reaction SMILES: C1([C:7]2[O:11][C:10]([C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=[O:15])=[N:9][N:8]=2)C=CC=CC=1.[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[CH2:21]([C:7]1[O:11][C:10]([C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[N:9][N:8]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: O=C(O)c1ccccc1-c1nnc(-c2ccccc2)o1
Product: COc1ccc(Cc2nnc(-c3ccccc3C(=O)O)o2)cc1

Procedure:
The same procedure is used as that for the preparation of 2-(5-phenyl-1,3,4-oxadiazole-2-yl) benzoic acid, Example 7, Method IIIb. The quantities of reagents used differ and p-anisoyl chloride was used in place of benzoyl chloride.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][O:63][C:64]1[CH:71]=[C:70]([N:72]2[CH2:77][CH2:76][CH:75]([N:78]3[CH2:83][CH2:82][N:81]([CH3:84])[CH2:80][CH2:79]3)[CH2:74][CH2:73]2)[CH:69]=[CH:68][C:65]=1[CH:66]=O>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:66]([C:65]3[CH:68]=[CH:69][C:70]([N:72]4[CH2:77][CH2:76][CH:75]([N:78]5[CH2:79][CH2:80][N:81]([CH3:84])[CH2:82][CH2:83]5)[CH2:74][CH2:73]4)=[CH:71][C:64]=3[O:63][CH3:62])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 60 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-benzaldehyde were reacted to produce the title compound (60%). 1H NMR (d-chloroform): 10.62 (br s, 1H), 8.22 (d, J=9 Hz, 1H), 7.98 (s, 1H), 6.66 (m, 2H), 6.50 (s, 1H), 6.33 (d, J=10 Hz, 2H), 5.07-5.19 (m, 2H), 4.03 (s, 3H), 3.90 (d, J=11 Hz, 2H), 3.49 (s, 2H), 3.17 (s, 1H), 2.89 (m, 4H), 2.65 (m, 4H), 2.46 (m, 4H), 232 (m, 1H), 2.31 (s, 3H), 1.97 (d, J=11 Hz, 2H), 1.60-1.79 (m, 3H). MS: 592.22 (M+H). HPLC retention time: 1.76 minutes (G Method).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+].C(OCC)(=O)C>CS(C)=O>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[CH:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2ccn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
6-Nitroindole (1.0 g) and benzyl chloride (2.2 g) are dissolved in dimethylsulfoxide (10 ml), and thereto is added potassium hydroxide (1.0 g), and the mixture is stirred at room temperature for 12 hours. To the mixture is added ethyl acetate, and the organic layer is washed with water, dried over sodium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give N-benzyl-6-nitroindole (1.4 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:34])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][N:27]=3)=[O:25])[CH:20]=[CH:19][C:18]=2[F:34])([CH:14]([F:16])[F:15])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)(C(F)F)COC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(C(=O)Nc2ccc(F)c([C@]3(C(F)F)COCC(N)=N3)c2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
((R)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester (44.47 g, 91.0 mmol) was dissolved in 450 ml DCM and mildly chilled with a rt water bath. TFA (150 ml) was added. The reaction was slightly exothermic. The mixture was stirred for 1.5 h at rt. The volatiles were removed with vacuum at rt. The residue was taken up in DCM and the procedure repeated twice. The residue was taken up in 3 L EtOAc and washed with 10% aqueous Na2CO3 and brine. The organic phase was dried with sodium sulfate and partially evaporated. iPrOH was added and the mixture chilled. The title compound was collected as snow-white crystals. Yield 30.56 g.
Reaction SMILES: [Br:1][CH:2]([CH2:7]Br)[C:3]([O:5][CH3:6])=[O:4].C[N+]([O-])(C)C.[CH3:14][O-:15].[Na+].[Na]>CO.C(OCC)C.C(O)(=O)C>[Br:1][CH:2]([CH2:7][O:15][CH3:14])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Br)CBr
Reactant: C[O-]
Agent: C[N+](C)(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CO
Product: COCC(Br)C(=O)OC

Procedure:
Methyl 2,3-dibromopropionate (21.9 g) and trimethylamine N-oxide (0.1 g) in methanol (8 ml) were cooled to −5° C. with stirring under an atmosphere of nitrogen. A solution of sodium methoxide [freshly prepared from sodium (2.25 g) and methanol (24 ml)] was added dropwise over 15 minutes to the mixture, which was maintained below 0° C. by cooling. On completion of the addition, the mixture was stirred for a further 30 minutes and acetic acid (1 ml) was added followed by diethyl ether (100 ml). The mixture was filtered to remove insoluble salts and the filtrate evaporated under reduced pressure to give an oil, which was re-dissolved in a small volume of diethyl ether and re-filtered. The filtrate was evaporated under reduced pressure to give the required product, 17.4 g, as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([CH3:14])=[N:9]2)([O-:3])=[O:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:33]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:33][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[N:9]=1
Reactant: Cc1ccc2c([N+](=O)[O-])cccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2nc(CBr)ccc12

Procedure:
A solution that consists of 800 mg (4.25 mmol) of 5-nitro-2-methylquinoline in 20 ml of tetrachloromethane is mixed with 11 mg (0.04 mmol) of benzoyl peroxide and 794 mg (4.46 mmol) of N-bromosuccinimide. The reaction mixture is allowed to reflux for 8 hours in the presence of UV light. Insoluble components are filtered off, and the filtrate is concentrated by evaporation. After purification on silica gel with hexane-ethyl acetate (0–100%), 320 mg (28% of theory) of the product is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([N:29]5[CH:33]=[CH:32][N:31]=[N:30]5)[CH:24]=4)[CH2:21][C:20](=[O:35])[NH:19][C:9]=3[CH:10]=2)[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnn3)c2)=Nc2ccc(-n3cccc3)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-pyrrol-1-yl-phenyl}-carbamic acid tert.-butyl ester (Example M20) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (36 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8].[CH3:13]O>>[ClH:3].[CH3:13][O:11][C:10](=[O:12])[CH:6]([CH:7]([CH3:9])[CH3:8])[NH2:5]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CC(C)C(N)C(=O)O
Product: COC(=O)C(N)C(C)C
Product: Cl
Reaction time: 0.33 h

Procedure:
Methanol (50 ml) is cooled to −15° C., then thionyl chloride (21.2 g) is added dropwise to the methanol, and the solution is stirred for 20 minutes. DL-Valine is added to the solution, and the mixture is stirred overnight. The reaction mixture is concentrated under reduced pressure, and diethyl ether is added to the resulting residue to precipitate crystals. The precipitated crystals are filtered off to give the titled reference compound (8.68 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]([OH:9])=O)=[CH:2]1.C(Cl)(=O)C(Cl)=O.[NH2:16][C:17]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>ClCCl.CN(C)C=O>[Cl:27][C:25]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([NH:16][C:7](=[O:9])[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:26]=1
Reactant: O=C(O)Cc1ccsc1
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)cc1NC(=O)Cc1ccsc1
Reaction time: 1 h
Yield: 40.4 %

Procedure:
To a solution of thiophene-3-acetic acid (1.4 g, 10 mmol) in dichloromethane (40 ml) was added oxalyl chloride (1.74 ml, 20 mmol) and dimethylformamide (catalytic, 3 drops) and the reaction stirred for 1 h. The solvent was evaporated and the residue co-evaporated with toluene (3×20 ml). The resulting acid chloride was dissolved in 1,2-dichloroethane (40 ml), methyl 2-amino-4-chlorobenzoate (1.5 g, 8 mmol) added and the reaction refluxed for 2 h. The residue remaining on evaporation of the solvent was triturated with diethyl ether to afford methyl 4-chloro-2-(3-thienyl)acetamidobenzoate as a tan solid (1 g), m.p. 96°-97° C. To a solution of the foregoing amide (0.5 g, 1.6 mmol) in tetrahydrofuran (25 ml) was added a solution of potassium hexamethyldisilazide in toluene (0.5M, 4 mmol) and the reaction stirred for 2 h. Methanol (5 ml) was added and the solvent evaporated. The residue was partitioned between aqueous sodium hydroxide (1M, 20 ml) and diethyl ether (20 ml), and the aqueous layer acidified with hydrochloric acid (5M). The resultant precipitate was collected and recrystallised from dimethylformamide/water to afford the title compound as a white solid; m.p. 341°-344° C. (from DMF/H2O) (Found: C, 55.07; H, 2.86; Cl, 12.94; N, 5.16; S, 11.42; C13H8ClNO2S, 0.5 H2O requires C, 55.32; H, 3.03, Cl, 12.56; N, 4.96; S, 11.36%); δ(DMSO-d6) 7.22 (1H, dd, J=8.6 and 2 Hz, 6-H), 7.31 (1H, s, 8-H), 7.43 (1H, d, J=4.9 Hz, 5'-H), 7.49-7.51 (1H, m, 4'-H), 7.76 (1H, s, 2'-H), 7.98 (1H, d, J=8.6 Hz, 5-H), 11.55 (1H, s, NH); m/z 277 (M+).