Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([OH:15])=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2].Cl[CH2:17][CH2:18][CH2:19][OH:20].C(O)(C)C>CC(OC)(C)C>[CH2:1]([O:3][C:4]1[C:5]([O:15][CH2:17][CH2:18][CH2:19][OH:20])=[CH:6][C:7]2[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=2[CH:14]=1)[CH3:2]
Reactant: CCOc1cc2ccc(=O)oc2cc1O
Reactant: OCCCCl
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CCOc1cc2ccc(=O)oc2cc1OCCCO
Yield: 69 %

Procedure:
Method K; starting materials: 6-ethoxy-7-hydroxy-2H-1-benzopyran-2-one and 3-chloro-1-propanol; yield 69%; fusion point 96°-98° C. (from isopropanol and TBME).
Reaction SMILES: [C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH:11]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(NCC)C>CN(C=O)C>[C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH2:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)OCc1cccc2c1Cc1ccccc1-2)=NNC(N)=O
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(C[C@H](N)C=O)=NNC(N)=O

Procedure:
(3S)-3-(1-Fluorenylmethyloxycarbonylamino)-4-oxobutyric acid tert-butyl ester semicarbazone (210 mg, 0.45 mol, Prepared in a similar manner to the benzyloxycarbonyl analog in Graybill et al., Int. J. Protein Res., 44, pp. 173-82 (1994).) was dissolved in 10 ml of DMF and 2 ml of diethylamine and stirred for 2 h. The reaction was concentrated in vacuo to give (3S)-3-amino-4-oxobutyric acid tert-butyl ester semicarbazone. The 0° C. solution of the above residue and 603a (200 mg, 0.42 mmol) in 5 ml of DMF and 5 ml of CH2Cl2 was treated with 1-hydroxybenzotriazole (57 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol). The reaction was stirred at RT for 18 h, poured onto EtOAc (75 ml) and washed with aq. 0.3 N KHSO4, sat. aq. NaHCO3 and sat. aq. NaCl, dried over NaSO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0% to 4% MeOH/0.1% NH4OH/CH2Cl2) to give 240 mg (83%) of 604a.
Reaction SMILES: [CH2:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[S:3][N:2]1[NH:14][C:15]([N:17]1[CH:21]=[CH:20]N=C1)=[S:16])=[CH:10][CH:9]=[CH:8][CH:7]=3.[C:22]1(CCN)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O>[C:22]1([CH2:20][CH2:21][NH:17][C:15]([NH:14][N:2]2[CH2:1][C:5]3[C:6]4[C:11]([CH:12]=[CH:13][C:4]=3[S:3]2)=[CH:10][CH:9]=[CH:8][CH:7]=4)=[S:16])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCc1ccccc1
Reactant: S=C(NN1Cc2c(ccc3ccccc23)S1)n1ccnc1
Solvent: CN(C)C=O
Product: S=C(NCCc1ccccc1)NN1Cc2c(ccc3ccccc23)S1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
A solution of 1-[(2-naptho[1,2]thiazolyl)-thiocarbamoyl] imidazole (1.6 g, 5 mmol) and 2-phenylethylamine (0.62 g, 5.2 mmol) in N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1 h, the reaction was cooled to room temperature and the solvent removed in vacuo. The residue was crystallized from ethyl acetate to provide 1.5 g (82%) of the titled product: IR (KBr, cm-1) 3171, 3027, 1581, 1521, 1213, 695; 1H NMR (300 MHz, DMSO-d6) δ 11.7 (br s, 1H), 9.9 (br s, 1H), 8.25 (d, J=8 Hz, 1H), 8.0 (d, J=8 Hz, 2H), 7.8 (d, J=8 Hz, 1H), 7.6-7.2 (m, 7H), 3.95 (m, 2H), 3.05 (t, J=7 Hz, 2H); MS (FD) m/e 364 (M+); UV (EtOH) 340 nm (ε=23922), 325 nm (ε=19262), 313 nm (ε=20808), 245 nm (ε=39665), 209 nm (ε=36141). Anal. Calcd for C20H17N3S2 : Theory: C, 66.09; H, 4.71; N, 11.56. Found: C, 65.86; H, 4.84; N, 11.48.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][CH:41]([C:43](O)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:23]1([C:29]2[C:30]3[CH:31]=[CH:32][C:33]([C:50]([O:52][CH3:53])=[O:51])=[CH:34][C:35]=3[N:36]3[CH2:42][CH:41]([C:43]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[O:44])[CH2:40][C:39]4[CH:46]=[CH:47][CH:48]=[CH:49][C:38]=4[C:37]=23)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Cc1ccccc1-3
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCOCC1)Cc1ccccc1-3
Temperature: 22 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
TBTU (69 mg, 0.22 mmol) was added to a stirred solution of racemic 14b (60 mg, 0.0.144 mmol), morpholine (19 μL, 0.22 mmol), and N,N-diisopropylethylamine (300 μL, 1.7 mmol) in DMF (3 mL). The mixture was shaken at 22° C. for 18 hr. The resulting solution was injected on a Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave methyl 13-cyclohexyl-6,7-dihydro-6-(morpholinylcarbonyl)-5H-indolo[2,1-a][2]benzazepine-10-carboxylate as a colorless solid (60 mg, 86%). ESI-MS m/z 487 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH:24]([CH3:26])[CH3:25]>>[CH:24]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([O:13][CH2:14][C@@H:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:9][CH:8]=2)=[CH:21][CH:22]=1)([CH3:26])[CH3:25]
Reactant: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(O)cc2)nc1
Reactant: CC(C)Br
Product: CC(=O)N[C@@H](C)COc1ccc(Oc2ccc(OC(C)C)cc2)nc1

Procedure:
N—{(S)-2-[6-(4-Hydroxyphenoxy)pyridin-3-yloxy]-1-methylethyl}acetamide (33 mg, 0.1 mmol) and 2-bromopropane (16 mg, 0.13 mmol) were reacted in analogy to example 1a. Yield: 23 mg (62%), M+H+: 345.19.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[C:18](=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[N:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(F)nc1F

Procedure:
To 2,6-difluoro-nicotinic acid (59, 5.60 g, 0.0352 mol) in methanol (60.0 mL) was added concentrated sulfuric acid (1.0 mL, 0.019 mol). The reaction was heated to reflux overnight, then poured into water, basified with 1M potassium carbonate to pH around 9, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a yellow oil (60, 3.5 g, 57.0%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=O)=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:76][CH2:77][CH2:78][O:79][CH2:80][CH2:81][O:82][CH2:83][CH2:84][O:85][CH2:86][CH2:87][NH2:88]>O1CCCC1>[NH2:88][CH2:87][CH2:86][O:85][CH2:84][CH2:83][O:82][CH2:81][CH2:80][O:79][CH2:78][CH2:77][NH:76][C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:37]
Reactant: NCCOCCOCCOCCN
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCOCCOCCOCCN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 20 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1, 100 mg, 162 μmol), HBTU (61.5 mg, 162 μmol) and Hunig's base (105 mg, 142 μL, 811 μmol) were combined with dry tetrahydrofuran (2 mL) to give an off-white suspension at room temperature. It was stirred at room temperature for 30 min. 1,11-Diamino-3,6,9-trioxaundecane (15.6 mg, 15.2 μL, 81.1 μmol) was added. After stirring at room temperature overnight, the reaction mixture was absorbed on small amount of silica gel, loaded on a 24 g pre-packed silica gel column and eluted with ethyl acetate to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(2-{2-[2-(2-amino-ethoxy)-ethoxy]-ethoxy}-ethylcarbamoyl)-2-methoxy-phenyl]-amide, dimer as white solid (148 mg, 66% yield). LCMS (ES+) m/z calcd. for C70H74Cl4F4N8O9 [(M+H)+]: 1387. found: 1387.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[CH:9]=2)[CH2:3]1.O=S(Cl)[Cl:28]>C(Cl)(Cl)Cl>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11]([CH3:24])[C:10](=[O:25])[C:9]=2[Cl:28])[CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)cc(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(Cl)c(N2CCC[C@@H](N)C2)n(Cc2ccccc2C#N)c1=O

Procedure:
Compound 4 (40 mg, 0.1 mmol) in CHCl3 (2 mL) was treated with SOCl2 (200 μL) at 100° C. for 30 min, concentrated, and then purified by LC-MS to give the title compound 7. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): δ 7.73 (d, J=7.6 Hz, 1 H), 7.64 (t, J=7.6 Hz, 1 H), 7.45 (t, J=7.6 Hz, 1 H), 7.14 (d, J=8.1 Hz, 1 H), 5.32-5.42 (m, 2 H), 3.43 (s, 3 H), 3.33-3.40 (m, 2 H), 3.17 (m, 2 H), 2.87 (s, 1 H), 2.08 (m, 1 H), 1.70 (m, 1 H), 1.32-1.43 (m, 2 H). MS (ES) [m+H] calc'd for C18H21ClN5O2, 374.1; found, 374.1.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:21][CH3:22])=[C:16](B(O)O)[CH:17]=1)=[O:11].C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(COC)OC>[CH3:22][O:21][C:15]1[C:16]([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=2[CH3:9])=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][CH:14]=1
Reactant: Cc1cccc(C)c1Br
Reactant: COc1ccc(C=O)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: COc1ccc(C=O)cc1-c1c(C)cccc1C
Temperature: 80 °C
Reaction time: 25 h

Procedure:
In an atmosphere of nitrogen, tetrakis(triphenylphosphine)palladium was added to a mixture of 2-bromo-1,3-dimethylbenzene, (5-formyl-2-methoxyphenyl)boronic acid, a 1 M sodium carbonate aqueous solution, ethanol and dimethoxyethane, followed by stirring at 80° C. for 25 hours to obtain 6-methoxy-2′,6′-dimethylbiphenyl-3-carbaldehyde.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1)[CH3:5].C(Cl)(Cl)Cl.[CH3:24][NH:25][C:26]([NH2:28])=[S:27].C(=O)(O)[O-].[Na+]>CO.[Na+].[Cl-]>[CH3:24][NH:25][C:26]1[S:27][CH:2]=[C:3]([CH:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]([F:18])[CH:7]=2)[CH3:5])[N:28]=1
Reactant: CC(C(=O)CCl)c1ccc(-c2ccccc2)c(F)c1
Reactant: CNC(N)=S
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNc1nc(C(C)c2ccc(-c3ccccc3)c(F)c2)cs1
Yield: 70 %

Procedure:
A mixture of (+)-1-chloro-3-(2-fluoro-4-biphenylyl)-2-butanone (27.7 mg, 0.1 mmol; [α]D25 ° C.+180° (c=0.744, CHCl3), N-methylthiourea (9 mg, 0.1 mmol) and sodium bicarbonate (9.2 mg, 0.11 mmol) in methanol (1 ml) was stirred at room temperature for 28 hr and the mixture was diluted with NaCl aq., then extracted with ethyl acetate. The extracts were dried with magnesium sulfate and evaporated under reduced pressure to a residue, which was chromatographed to afford (+)-2-methylamino-4-(1-(2-fluoro-4-biphenylyl)ethyl)thiazole (21.9 mg, 70% yield): [α]D25 ° C.+10.7° (c=0.15, CHCl3); 70% ee.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#N)[CH:7]=1)[CH3:2].C(O)=[O:16]>[Al].[Ni]>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]=[O:16])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Product: CCOC(=O)Cc1cccc(C=O)c1
Temperature: 100 °C

Procedure:
To a solution of (3-cyano-phenyl)-acetic acid ethyl ester (4.8 g, 25.4 mmol) in 75% aqueous formic acid was added nickel-aluminum alloy (4.6 g). The mixture was heated at reflux (100° C.) for 2.25 h. The reaction mixture was cooled and was filtered through Celite with the aid of boiling EtOH. The filtrate was diluted with H2O and the product was extracted into CHCl3 (3×). The organic solution was stirred with saturated NaHCO3 solution until a pH of 8 was attained. The organic solution was dried over MgSO4, filtered, and concentrated. The product was purified by flash chromatography (5:1 hexanes/EtOAc) to afford the title compound (3.33 g). 1H NMR (400 MHz, CDCl3) δ 7.76-7.79 (m, 2H), 7.47-7.57 (m, 2H), 4.15 (q, 2H), 3.69 (s, 2H), 1.25 (t, 3H); MS 193 (M+1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:11]([O:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]#[CH:9])[C:3]1=[O:10])(=[O:13])[CH3:12]
Reactant: C#CCN1CC[C@@H](O)C1=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCN1CC[C@@H](OC(C)=O)C1=O

Procedure:
The title compound is prepared by the procedure of Example 52 using 19.6 g of (R)-3-hydroxy-1-(2-propynyl)-2-pyrrolidinone, 26.6 ml of acetic anhydride, 17 ml of pyridine, 0.6 g of 4-(dimethylamino)pyridine and 200 ml of methylene chloride to give 23.4 g of the desired product as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[S:19][C:18]([S:20](Cl)(=[O:22])=[O:21])=[CH:17][CH:16]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:20]([C:18]1[S:19][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=2)=[CH:16][CH:17]=1)(=[O:21])=[O:22]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)c1Br
Yield: 40 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and 5-(2-pyridyl)thiophene-2-sulphonyl chloride in 40% yield. Purification was achieved by recrystallization from ethyl acetate to give a crystalline solid, m.p. 186-188° C.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:28])([CH3:27])[C:14]([CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17](OCC)=[O:18])=[O:15])=[CH:9][CH:8]=1.O>CCCCCCC>[Cl:6][C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][CH:8]=1)[C:13]([CH3:27])([CH3:28])[C:14](=[O:15])[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:17]2[OH:18]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCCCCCC
Product: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
Concentrated H2SO4 (5.0 mL, 18.0M) was cooled to −4° C. and treated with diethyl 2-(2-(4-chlorophenyl)-2-methylpropanoyl)malonate (1.00 g, 2.93 mmol). The resulting green solution was warmed to room temperature and allowed to stir for 1 hour. The solution was then poured into a 0° C. chilled mixture of water (10 mL) and heptane (5 mL). The resulting precipitate was collected by vacuum filtration, washed with cold water (10 mL) and heptane (1 mL). The product was dried at 40° C. overnight under vacuum to give 0.69 g of the title compound. MS m/e=295.2 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[NH4+].[Cl-].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:22]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:23]
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 20.7 %

Procedure:
To a degassed solution 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (22.2) (1.2 g, 3.52 mmol) in DMF (10 mL) was added Pd(PPh3)4 (610 mg, 0.528 mmol). The solution was stirred for 20 min, then tributyl(vinyl)stannane (1.227 g, 3.87 mmol) was added. The reaction mixture was heated at 120° C. for 5 h. Aqueous NH4Cl solution was added to quench the reaction, followed by addition of EtOAc. The mixture was filtered through celite and the filtrate was washed with saturated NaHCO3 and NH4Cl solutions. The organic layer was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified with Analogix system on silica gel (hexanes:EtOAc) to afford 210 mg (20%) of the title compound. LCMS (method B): [MH]+=288, tR=2.05 min.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:14](=[O:16])[CH3:15])[CH:8]=[CH:7]2>C(Cl)Cl>[Br:1][CH2:15][C:14]([C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([Br:3])[CH:5]=2)[CH:10]=1)=[O:16]
Reactant: CC(=O)c1ccc2cc(Br)ccc2c1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(CBr)c1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of bromine (0.682 mL, 13.3 mmol) in DCM (20 mL) was added to a solution of 1-(6-bromonaphthalen-2-yl)ethanone (3.30 g, 13.3 mmol) (>90% purity) in DCM (60 mL) and the reaction was stirred at rt overnight. The reaction mixture was concentrated to yield 2-bromo-1-(6-bromonaphthalen-2-yl)ethanone (4.35 g) as an off white solid which was used without further purification. LC-MS retention time 2.177 min; m/z 342.92 (MNa+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10u C18 2.0×30 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 1 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.49 (s, 1 H), 8.03-8.10 (m, 2 H), 7.86 (d, J=8.5 Hz, 1 H), 7.85 (d, J=8.8 Hz, 1 H), 7.67 (dd, J=8.8, 2.0 Hz, 1 H), 4.56 (s, 2 H).
Reaction SMILES: [CH:1]1([C:7]2([C:13](Cl)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16][CH:17]1[CH2:22][NH:21][C:20](=[N:23][N+:24]([O-:26])=[O:25])[NH:19][CH2:18]1.CN(C=O)C>C(#N)C>[CH:1]1([C:7]2([C:13]([O:16][CH:17]3[CH2:18][NH:19][C:20](=[N:23][N+:24]([O-:26])=[O:25])[NH:21][CH2:22]3)=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=[N+]([O-])N=C1NCC(O)CN1
Reactant: O=C(Cl)C1(C2CCCCC2)CCCCC1
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(OC1CNC(=N[N+](=O)[O-])NC1)C1(C2CCCCC2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-cyclohexylcyclohexane-1-carbonyl chloride (2.1 g) in acetonitrile (30 ml), 5-hydroxy-2-nitroiminohexahydropirimidine (1.28 g) was added portionwise. The mixture was stirred at room temperature overnight, then DMF (10 ml) was added and the mixture was heated to 50° C. for 24 hours. The reaction was quenched with water. The precipitate was collected, dried and triturated with diethyl ether to afford 0.93 g of 2-nitroiminohexahydropyrimidin-5-yl 1-cyclohexylcyclohexane-1-carboxylate.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH:16]2[CH2:20][C:19]3[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:18]=3[O:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:25][C:22]1[CH:23]=[CH:24][C:18]2[O:17][CH:16]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:15])[CH2:20][C:19]=2[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2Cc3cc(F)ccc3O2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(C1Cc2cc(F)ccc2O1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
In a 100 ml round-bottomed flask was added 4-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (1.8 g, 5.1 mmol), 50 ml of dichloromethane, and 2 ml of trifluoroacetic acid. The solution was stirred at room temperature overnight. The solution was made basic with the addition of saturated aqueous sodium bicarbonate. The mixture was then extracted with 4×50 ml of dichloromethane. The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum to afford 1.2 grams of the desired amine as a brown oil (94%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[N:4][OH:5].S(=O)(=O)(O)O.[CH2:11]=[C:12]([CH3:14])[CH3:13].C(=O)([O-])O.[Na+]>C(OCC)C>[C:12]([O:5][N:4]=[CH:3][CH2:2][Cl:1])([CH3:14])([CH3:13])[CH3:11]
Reactant: C=C(C)C
Reactant: ON=CCCl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)ON=CCCl

Procedure:
Then, 0.47 g of chloroacetoaldehyde oxime, 0.1 ml of concentrated sulfuric acid, and 10 ml of diethyl ether are placed in a reaction vessel, into which isobutene gas is blown with stirring under ice cooling, and the stirring is further continued at room temperature. After completion of the reaction, the reaction mixture is slowly poured into saturated aqueous sodium hydrogencarbonate solution, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with 10% aqueous sodium hydroxide solution and water in this order, dried over anhydrous magnesium sulfate, and concentrated, which affords chloroacetoaldehyde O-tert-butyloxime.
Reaction SMILES: Cl[Si](C)(C)C.[BH4-].[Li+].[CH3:8][C:9]([CH3:36])([P:33](=[O:35])=[O:34])[N:10]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([O:29][CH2:30][C:31]#[N:32])[CH:23]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])(=[O:13])=[O:12].O>O1CCCC1>[CH3:8][C:9]([CH3:36])([P:33](=[O:35])=[O:34])[N:10]([C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([O:29][CH2:30][CH2:31][NH2:32])[CH:23]=1)[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])(=[O:12])=[O:13]
Reactant: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCC#N)c1)C(C)(C)P(=O)=O
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1S(=O)(=O)N(c1cc(C)cc(OCCN)c1)C(C)(C)P(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
3.3 ml Chlorotrimethylsilane was added dropwise under nitrogen and while cooling on ice to 0.29 g (13.2 mmol) lithium borohydride in 5 ml tetrahydrofuran, it was stirred for 1 h at room temperature, a solution of 0.93 g (2.2 mmol) N-(dimethyloxophosphinyl-methyl)-N-(3-cyanomethoxy-5-methyl-phenyl)-2-methoxy-benzenesulfonamide in 5 ml tetrahydrofuran was added dropwise, it was stirred for 1 h at room temperature, water was added dropwise, the solvent was removed in a vacuum, it was taken up in a small amount of dichloromethane and filtered over silica gel (dichloromethane:methanol=9:1), the solvent was removed in a vacuum and 900 mg (91%) N-(dimethyloxophosphinyl-methyl)-N-[3-(2-amino-ethoxy)-5-methyl-phenyl]-2-methoxy-benzenesulfonamide was obtained as an oil. MS (m/e)=426.