Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=NC=CC=2)N([O:10][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=O)N=1.[CH3:43][NH2:44]>CC(N(C)C)=O>[CH3:43][NH:44][C:11]([C:13]1[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]2\[C:21](=[O:41])[NH:22][C:23]3[C:28]\2=[CH:27][C:26]([S:29]([CH2:32][C:33]2[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=2[Cl:39])(=[O:30])=[O:31])=[CH:25][CH:24]=3)[NH:15][C:14]=1[CH3:42])=[O:10]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: CN
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added methylamine (2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat. NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[NH:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Br>CN(C=O)C>[Br:11][C:8]1[N:7]([CH2:23][C:22]2[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:21]=2[Cl:20])[C:6]2[C:5](=[O:12])[NH:4][C:3](=[O:13])[N:2]([CH3:1])[C:10]=2[N:9]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: Fc1cccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1c(F)cccc1Cl
Temperature: 60 °C
Yield: 76 %

Procedure:
A solution of 3-methyl-8-bromoxanthine (1.5 g, 6.1 mmol, Klein, J. P. PCT Int. Appl. WO 0061583, 2000) and K2CO3 (0.84 g, 6.1 mmol) in 6 mL DMF was treated with 2-chloro-6-fluorobenzyl bromide. The reaction mixture was heated to 60° C. for 2 hr, cooled, and poured onto ice water. The solid precipitate was filtered and dried to yield 1.8 g (76% yield) of a white solid: 1H NMR (DMSO, 400 MHz) 7.43-7.36 (m, 1H), 7.34-7.30 (m, 1H), 7.22-7.15 (m, 1H), 5.67 (s, 2H), 3.29 (s, 3H); MS (AP+) m/e 389 (MH+).
Reaction SMILES: [SH:1][CH2:2][CH:3]1[CH2:7][O:6][C:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:4]1.[CH2:22]([C:25]1[C:37]([OH:38])=[C:36]([C:39](=[O:41])[CH3:40])[CH:35]=[CH:34][C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br)[CH2:23][CH3:24]>C(C(C)=O)C>[C:39]([C:36]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:1][CH2:2][CH:3]2[CH2:7][O:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[S:4]2)=[C:25]([CH2:22][CH2:23][CH3:24])[C:37]=1[OH:38])(=[O:41])[CH3:40]
Reactant: CCCc1c(OCCCCCBr)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)OCC(CS)S1
Solvent: CCC(C)=O
Product: CCCc1c(OCCCCCSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O
Yield: 93 %

Procedure:
The reaction of the mercaptan from Example 1 (2.0 g, 0.006 mol) and 5-(2-n-propyl-3-hydroxy-4-acetylphenoxy)-1-bromopentane (described in U.S. Pat. No. 4,565,882, Example 1) (2.1 g. 0.06 mol) in methyl ethyl ketone (20 ml) was carried out and worked up in the same manner as described in Example 2. After chromatography on silica gel using 25% ethyl acetate/hexane as eluent, 3.3 g (93%) of the title compound was obtained as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:21])[C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14]([S:16][CH3:17])=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>C(O)(C)C>[CH3:22][S:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:2]2[N:7]=[C:6]([N:8]([CH3:21])[C:9]3[CH:20]=[CH:19][C:12]4[N:13]([CH3:18])[C:14]([S:16][CH3:17])=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)(=[O:24])=[O:25]
Reactant: CSc1nc2cc(N(C)c3ccnc(Cl)n3)ccc2n1C
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Solvent: CC(C)O
Product: CSc1nc2cc(N(C)c3ccnc(Nc4ccc(CS(C)(=O)=O)cc4)n3)ccc2n1C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-Chloro-pyrimidin-4-yl)-methyl-(1-methyl-2-methylsulfanyl-1H-benzoimidazol-5-yl)-amine (3.19 g, 10 mmol), 4-Methanesulfonylmethyl-phenylamine (1.85 g, 10 mmol) and (833 ul, 12N, 10 mmol) was refluxed in isopropanol (100 ml) overnight. The mixture was then concentrated to dryness and the residual was taken into MeOH and stirred with NaHCO3 (3 g) at room temperature for 20 min. and filtered, the filtrate was concentrated and the residual was purified by silica flash gave 3.35 g as a pale yellow solid: LC/MS(m/e) 469.2 [M+H]+, Rt at 1.37 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:56][C:57]([F:61])([F:60])[CH2:58][NH2:59]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:59][CH2:58][C:57]([F:61])([F:60])[F:56])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (69 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and 2,2,2-trifluoroethylamine (17.3 μL, 0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (30 mg, 35%) as a white solid. MS: m/e=426.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11]([NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:13][C:11](=[O:12])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 74.6 %

Procedure:
4-chlorobenzeneboronic acid (2.05 eq, 2.05 g), N-boc tyramine (1 eq, 6.55 mmol, 1.60 g), cooper(II)-acetate (1.01 eq, 1.20 g) and pyridine (5 eq, 2.64 ml) were dissolved in 70 ml of dry DCM. In the solution were added 4 Å molecular sieves (3 g) and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was then filtered over a celite pad, it was diluted with 150 ml of diethyl ether and was subsequently washed with 150 ml of 0.5 N HCl water solution, 150 ml of water and 150 ml of brine. The organic phase was dried, the solvent was evaporated and the resulting crude was purified by chromatography on BIOTAGE SP1 purification device using 50 g normal phase silica SNAP column and cyclohexane/EtOAc solvent system (gradient 5-30% of EtOAc in 20 column volumes). Solvent from the gathered fractions of appropriate composition was evaporated and obtained was {2-[4-(4-chloro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (1.7 g, yield=68.14%, purity=94%). MS: [M−H]−=346.13 1H NMR (300 MHz; CDCl3) δ/ppm 1.42 (s, 9H), 2.75 (t, J=7.0 Hz, 2H), 3.35 (m, 2H), 6.87-6.95 (m, 4H), 7.14 (d, J=8.45 Hz, 2H), 7.22-7.28 (m, 2H)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[N:24]([CH3:25])[N:23]=[CH:22][C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].C(#N)C.[OH2:39]>>[C:1]([O:5][C@@H:6]([C:9]1[C:27]([CH3:28])=[CH:26][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[C:18]4[N:24]([CH3:25])[N:23]=[CH:22][C:19]4=[N:20][CH:21]=3)[S:15][C:11]=2[C:10]=1[C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C:7]([OH:39])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O
Reactant: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Solvent: CC#N
Product: Cc1cc2nc(-c3cnc4cnn(C)c4c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)benzo[d]thiazol-6-yl)ethanol (50 mg, 0.099 mmol) in acetonitrile/water (2 mL/0.5 mL) was added CrO3/H5IO6 (0.439M, 1.1 mL, 0.483 mmol) and CrO3 (20 mg, 0.198 mmol). The reaction solution was stirred at room temperature for 1 h and quenched with 5% Na2S2O3 solution. The mixture was extracted with ethyl acetate, washed with water and brine. The organic solution was dried and concentrated to give crude which was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+: calc'd for C27H25ClN4O3S: 521.14 (M+H+); Found: 521.2 (M+H+), 1H NMR (400 MHz, CD3OD) δ 9.20 (d, J=8 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.88 (s, 1H), 7.71-7.59 (m, 4H), 5.27 (s, 1H), 4.16 (s, 3H), 2.62 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]([NH:14][CH2:15][CH2:16][NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1)#[N:2].C(N(CC)CC)C.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34]>C(Cl)Cl>[CH3:12][C:10]1([CH3:13])[CH2:9][CH:8]([N:14]2[CH2:15][CH2:16][N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:33]2=[O:34])[C:7]2[CH:24]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11]1
Reactant: CC1(C)CC(NCCNc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CC(N2CCN(c3ccccc3)C2=O)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of N-(6-cyano-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-4yl)-N'-phenylethylene-diamine (0.36 g, 1.12 mmole, from Example 21, part A) and triethylamine (0.12 g, 1.18 mmole) in methylene chloride (4 ml) cooled to 0° C. was added a solution of 4-nitrophenyl chloroformate (0.24 g, 1.18 mmole) dissolved in methylene chloride (3 ml). The reaction mixture was stirred at room temperature for four hours. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate and 5% aqueous HCl solution. The organic phase was washed with 2N NaOH solution, saturated NaCl solution, dried over MgSO4 and solvent evaporated to obtain 420 mg of an orange gum. The crude product was chromatographed on silica eluting with hexane/ethyl acetate (4:1) to obtain 0.30 g of the title compound as a pure white solid. m.p.=166°-168° C. 1H NMR (DMSO-d6) δ7.61 (m, 4H), 7.35 (m,2H), 7.03 (m, 1H), 6.95 (d, J=8.21 Hz, 1H), 5.21 (dd, J=6.45 and 11.73 Hz, 1H), 3.88 (m, 2H), 3.36 (m 1H), 3.14 (m, 1H), 2.03 (m, 2H), 1.47 (s, 3H), 1.33 (s, 3H); 13C NMR (DMSO-d6) δ158.08, 157.13, 140.58, 132.86, 131.56, 128.63, 121.86, 121.63, 119.15, 118.52, 117.05, 102.54, 77.31, 44.68, 42.06, 36.56, 34.06, 29.36, 24.01; MS: (M+H)+ @348.
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][C:23]([CH:20]4[CH2:22][CH2:21]4)=[O:24])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(O)C1CC1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Product: O=C(Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2)C1CC1
Yield: 41.3 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and cyclopropanecarboxylic acid (80 mg, 0.93 mmol) according to the procedure described for example 93. Obtained the title compound as an off-white foam (104 mg, 41%), MS (ISP) m/e=328.4 [(M+H)+].
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[N:13]1([CH2:11][C:3]2[CH:2]=[N:1][C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: O=Cc1cnc2c(c1)CCCC2
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: c1nc2c(cc1CN1CCOCC1)CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A 100 mL three-neck round bottom flask equipped with a nitrogen inlet, bubbler, and glass stopper is charged with 1,2-dichloroethane (45 mL), 5,6,7,8-tetrahydroquinoline-3-carbaldehyde (Preparation 15, 2.39 g) and morpholine (1.42 mL). To the above solution is added NaBH(OAc)3 (5.01 g) in one portion. After 1 hour at room temperature, the reaction is quenched via slow addition of Na2CO3 (50 mL of a saturated aqueous solution). The resulting biphasic solution is stirred for two hours at room temperature then poured into methylene chloride (100 mL). The resulting layers are separated, and the organic layer is dried with Na2SO4, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography (10% methanol/CH2Cl2) to give 2.60 g (76%) of the title compound as an oil which crystallizes on standing. Physical characteristics: M.p. 40.9° C.; 1H NMR (CDCl3): δ8.24, 7.31, 3.68, 3.41, 2.88, 2.74, 2.41, 1.87, 1.78; 13C NMR (CDCl3) δ156.4, 147.5, 137.6, 131.9, 130.1, 66.9, 60.4, 53.5, 32.2, 28.7, 23.1, 22.7.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8](=NO)[CH3:9])[CH2:4][CH2:3]1.C(Cl)(=[O:14])C>C(N(CC)CC)C>[NH:2]1[CH2:7][CH:6]=[C:5]([C:8](=[O:14])[CH3:9])[CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC(=NO)C1=CCN(C)CC1
Solvent: CCN(CC)CC
Product: CC(=O)C1=CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 7.66 g of 1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone oxime, 6.8 ml of triethylamine, and 3.8 ml of acetyl chloride were stirred at room temperature overnight under a nitrogen atmosphere. Isolation of the product in the conventional manner produced 8.07 g of 1-(1,2,3,6-tetrahydro-4-pyridinyl)ethanone, O-acetyloxime which was converted to the hydrochloride salt, mp 104.5°-105.5° C.
Reaction SMILES: Cl[CH:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH:7]3[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]3[CH2:5][C:4]=2[NH:3]1.[CH:17]1([NH:23][CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CCCCCC.CCOC(C)=O>[CH:17]1([N:23]([CH3:24])[C:2]2[CH:11]=[CH:10][C:9]3[C:8](=[O:12])[CH:7]4[CH2:13][CH2:14][CH2:15][CH2:16][CH:6]4[CH2:5][C:4]=3[N:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CNC1CCCCC1
Reactant: O=C1C2=C(CC3CCCCC13)NC(Cl)C=C2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN(c1ccc2c(n1)CC1CCCCC1C2=O)C1CCCCC1
Yield: 52 %

Procedure:
A mixture of 2-chloro-2,5a,6,7,8,9,9a,10-octahydro-1H-benzo[g]quinolin-5-one (0.29 g, 1.23 mmol) and cyclohexyl(methyl)amine (1.39 g, 12.3 mmol) was stirred at 110° C. for 9.5 h (TLC control; hexane-EtOAc, 2:1). Then the mixture was separated by column chromatography on silica gel to give the title compound (0.2 g, 52%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si](C)(C)N[Si](C)(C)C.[Li].CO[C:23]([C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1)=O.Cl>O1CCCC1>[CH3:31][C:29]1[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=[C:25]([C:23]2[O:1][C:2]3[C:3]([C:8](=[O:10])[CH:9]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:30]=1
Reactant: CC(=O)c1ccccc1O
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(=O)c3ccccc3o2)ncc1[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A solution of 2′-hydroxyacetophenone (1.68 g, 12.39 mmol) in tetrahydrofuran (120 ml) under argon was cooled to −78° C. and treated dropwise with lithium hexamethyldisilazane (1M in tetrahydrofuran, 2.25 ml, 2.25 mmol). The solution was stirred at −78° C. for 1 hour and at −10° C. for 2 hours then cooled down to −78° C. and treated dropwise with a solution of 4-Methyl-5-nitro-pyridine-2-carboxylic acid methyl ester (WO2005/103003) (2.42 g, 12.39 mmol) in tetrahydrofuran (60 ml). The dark red solution was stirred at −78° C. for 1 hour then at room temperature for 18 hours. The mixture was poured into a ice-cold 1 N solution of hydrochloric acid (200 ml) and extracted several times with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated to dryness. The residue was dissolved in acetic acid (60 ml), treated with sulfuric acid (0.33 ml) and heated to 100° C. for 30 minutes. After cooling to room temperature, the solution was concentrated and the residue added with water and neutralized with a saturated solution of sodium hydrogenocarbonate. The precipitate was filtrated, washed with water and dried under vacuum to yield 2-(4-Methyl-5-nitro-pyridin-2-yl)-chromen-4-one (2.33 g, 66%) as a brown solid. The previous chromen-4-none (770 mg, 2.72 mmol) was treated with tert-butyl-hydroxylamine hydrochloride (685 mg, 5.45 mmol) in methanol (20 ml) at 130° C. for 30 minutes under microwave irradiation (method D, step 1) to yield the title compound (394 mg, 41%) after purification by silica gel flash chromatography (gradient cyclohexane/dichloromethane 0-80%) as a gold solid.
Reaction SMILES: [CH:1](=O)[CH3:2].[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:13].N1CCCCC1>CO>[CH:1](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:13])[CH3:2]
Reactant: CC=O
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: CC=C1C(=O)Nc2ccccc21

Procedure:
0.85 mL (15 mmol) acetaldehyde were added dropwise to 2.0 g (15 mmol) indolin-2-one and 0.20 mL piperidine in 20 mL methanol. The reaction mixture was refluxed for 3 h and then evaporated down. The residue was triturated in diisopropylether and suction filtered.
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([NH:30][NH2:31])=[O:29])=[CH:26][CH:25]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2].[CH2:39]=[NH:40]>CN(C=O)C>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=2)[N:8]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]3[O:29][C:39]([NH2:40])=[N:31][N:30]=3)=[CH:32][CH:33]=2)[C:7]=1[CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=N
Reactant: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(C(=O)NN)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccccn3)ccc2n1Cc1ccc(-c2nnc(N)o2)cc1
Temperature: 85 °C

Procedure:
To 4-[3-tert-Butylsulfanyl-2-(2,2-dimethyl-propyl)-5-(pyridin-2-ylmethoxy)-indol-1-ylmethyl]-benzoic acid hydrazide (0.05 g, 0.10 mmol) in DMF (1 mL) was added C-Di-imidazol-1-yl)-methyleneamine (0.08 g, 0.50 mmol), and the reaction was heated at 85° C. for 3 hours. The mixture was cooled to room temperature and partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified on silica gel (EtOAc:hexane gradient) to give the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=2)[C:5]#[N:6])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: N#Cc1ccnc(Cl)c1
Product: N#Cc1ccnc(N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.4 %

Procedure:
2-Chloro-isonicotinonitrile (80 g, 0.58 mol) and piperazine (199 g, 2.32 mol, 5 equiv) were combined and heated at 70 DC for 2.5 hours. The resulting suspension was cooled to room temperature and partitioned between a solution of 50% ethyl acetate/dichloromethane and water. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were concentrated in vacuo to about half the initial volume and ether was added. The suspension was stirred overnight, then filtered. The solid was dried under vacuum to give the desired product (31 g). The mother liquors were concentrated in vacuo and the residue was triturated with ether and filtered. The solid collected in this second batch was dried under vacuum and combined with the first batch to give the total amount of desired product (46 g, 42%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[C:12]([O:21][C:22]2[CH:23]=[N:24][C:25]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([Cl:28])[CH:27]=2)=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16](O)=[O:17].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:60][S:61]([NH2:64])(=[O:63])=[O:62]>ClCCl>[Cl:10][C:11]1[C:12]([O:21][C:22]2[CH:23]=[N:24][C:25]([O:29][C@@H:30]([CH3:35])[C:31]([F:34])([F:33])[F:32])=[C:26]([Cl:28])[CH:27]=2)=[CH:13][C:14]([F:20])=[C:15]([CH:19]=1)[C:16]([NH:64][S:61]([CH3:60])(=[O:63])=[O:62])=[O:17]
Reactant: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)O)cc2Cl)cc1Cl)C(F)(F)F
Reactant: CS(N)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
Diisopropylethyl amine (11.7 mL, 66.8 mmol) was added to a solution of (S)-5-chloro-4-((5-chloro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-3-yl)oxy)-2-fluorobenzoic acid (Preparation 299, 6.9 g, 16.7 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (9.5 g, 25.1 mmol) and methylsulfonamide (2.4 g, 25.1 mmol) in dichloromethane (125 mL). The reaction mixture was stirred at room temperature for 20 hours, then quenched with an aqueous solution of hydrogen chloride (2M, 50 mL). Organics were removed in vacuo and the aqueous residue was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The crude compound was purified by silica gel chromatography, eluting with dichloromethane:methanol (from 100:0 to 96:4), followed by reverse phase chromatography, eluting with acetonitrile:water (from 5:95 to 95:5) to provide the title compound as a white solid (4.8 g, 56%).