Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH3:13])[CH:6]=[CH:5]2.[CH3:14][C:15]1[CH:16]=[N:17][NH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN1C(=O)CCC1.[Cu]I>[CH3:13][N:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([N:17]3[CH:16]=[C:15]([CH3:14])[CH:19]=[N:18]3)[CH:3]=2)[C:8]1=[O:12]
Reactant: Cc1cn[nH]c1
Reactant: Cn1ccc2cc(Br)ccc2c1=O
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cnn(-c2ccc3c(=O)n(C)ccc3c2)c1
Yield: 52.7 %

Procedure:
6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol), 4-methyl-1H-pyrazole (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol) and K2CO3 (360.0 mg, 2.54 mmol) in NMP (3.0 mL) were microwaved at 195° C. for 5 h. Extractive work up with ethyl acetate followed by silica gel chromatography (PE:EA=5:1) gave the title compound of step 1 (160.0 mg, 52%) as a light yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.8 Hz, 1H), 7.84 (s, 1H), 7.83 (d, J=2.0 Hz, 1H), 7.74 (dd, J1=8.8 Hz, J2=2.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J=7.6 Hz, 1H), 6.52 (d, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.19 (s, 3H). LCMS: 240.0 (M+H)+.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:12][C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:28]([N:10]1[C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH2:14][CH2:13]2)[NH:12][C@@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]1=[O:25])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)C(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1

Procedure:
To a solution of 3-(S)-benzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one (1.0 g, 2.9 mmol) in 40 mL of dry THF there was added sodium hydride (90 mg, 3.8 mmol) at room temperature and under a blanket of nitrogen. Following stirring over a period of 1 h at RT benzyl chloride (1.47 g, 11.6 mmol) was slowly added dropwise and the mixture was then heated over a period of 12 h under reflux. Following the addition of an aqueous saturated HCl solution (20 mL), the reaction mixture was isolated by filtration and the filtrate was extracted with EE (3×15 mL), and the combined organic phases were dried over Na2SO4. Following removal, by distillation, of the solvent, there was obtained the crude product as a yellow oil. Further purification was carried out by column chromatography. The product 1,3-(S)-dibenzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.1 g (52%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:4][CH:3]=1.C(OCC)C.C(O[CH:21](OCC)[N:22]([CH3:24])[CH3:23])C>>[CH3:21][N:22]([CH3:24])[CH:23]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CCOC(OCC)N(C)C
Solvent: CCOCC
Product: CN(C)C=Nc1ccc(-c2c[nH]cn2)cc1

Procedure:
A solution of 3.18 gm of 4-(4-aminophenyl)-1-H-imidazole in 8.82 gm of N,N-dimethyl-formamide diethyl acetal was stirred at room temperature for two days. Addition of diethyl ether resulted in precipitation of the formamidine, which was collected by filtration.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C(#N)C.C(=O)=O.C([Li])CCC.CON(C)[C:24](=[O:27])[CH2:25][CH3:26]>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: c1cc2sccc2cn1
Reactant: CCC(=O)N(C)OC
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC(=O)c1cc2cnccc2s1
Temperature: -78 °C
Reaction time: 14 h
Yield: 82.7 %

Procedure:
To a stirring mixture of thieno[3,2-c]pyridine (1.0 g) in anhydrous tetrahydrofuran (50 mL) at −40° C. (acetonitrile-dry ice bath) was added a solution of n-butyllithium (1.6 M, 4.7 mL) in hexanes. The mixture was cooled to −78° C. followed by the subsequent addition of a solution of N-methoxy-N-methyl-propionamide (0.97 g) in anhydrous tetrahydrofuran (10 mL). The cold bath was removed and the reaction mixture was allowed to warm gradually to room temperature. The mixture was stirred overnight (14 hours). The mixture was treated with saturated aqueous ammonium chloride (150 mL). The mixture was then extracted with ethyl acetate (500 mL), and the extract was washed with brine solution (100 mL). The organic phase was dried over anhydrous potassium carbonate and was concentrated under reduced pressure, reconstituted in chloroform, and concentrated again under reduced pressure to afford the orange-brown semisolid (1.17 g). The semisolid was purified by flash silica chromatography using an Analogix silica column (115 g silica), eluting with 0-30% ethyl acetate/heptane, then 30-60% ethyl acetate/heptane. Concentration of fractions containing product gave 0.49 g of product. Starting material (0.45 g) was also isolated by evaporation of appropriate fractions.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([I:11])=[CH:7][N:6]2[C:12]=1[CH3:13].[CH3:14][O-:15].[Na+]>CO>[I:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:12]([CH3:13])=[C:3]([CH2:2][O:15][CH3:14])[N:4]=2)[CH:7]=1
Reactant: Cc1c(CCl)nc2ccc(I)cn12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCc1nc2ccc(I)cn2c1C
Temperature: 25 °C
Yield: 67.6 %

Procedure:
To a stirred solution of 2-(chloromethyl)-6-iodo-3-methylimidazo[1,2-a]pyridine (150 mg) in MeOH (2.5 ml) was added sodium methoxide (65 mg), and the resulting mixture was heated at reflux for 3 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The mixture was diluted with water, and extracted with EtOAc. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) to give the title compound (100 mg) as an off-white solid.
Reaction SMILES: Br[C:2]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]1Br.Cl[Si:16](C)([CH3:18])[CH3:17]>C1COCC1>[CH3:17][Si:16]1([CH3:18])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: BrC1C=CC=CC1(Br)c1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: C[Si]1(C)c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
1,2-Dibromobiphenyl (10 g, 1 eq, 0.032 mol) was placed in a flask, and THF (150 ml) was added thereto. Then, n-buthyllithium (24.1 ml, 1.2 eq, 0.038 mol) was gradually added at −78° C., the reaction mixture was stirred for 30 minutes, and chlorotrimethylsilane (4.1 g, 1.2 eq, 0.038 mol) was added thereto. The resultant solution was stirred for four hours and distilled water was added thereto, followed by stirring for about 10 minutes. The reaction solution was extracted with hexane, dried to remove the solvent and purified by column chromatography to give 5,5-dimethyl-5H-dibenzo[b,d]silole (5.17 g, yield=77%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Cl:13])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.S([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH3:26])=[CH:21][CH:20]=1)(O)(=O)=O.N1C2C(=CC=CC=2)C=CC=1>>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[C:5]([Cl:13])[CH:6]=1)[N:3]=[C:2]([N:25]([C:22]1[CH:23]=[CH:24][C:19]([OH:18])=[CH:20][CH:21]=1)[CH3:26])[CH:11]=[CH:10]2
Reactant: Clc1cc(Cl)c2nc(Cl)ccc2c1
Reactant: CNc1ccc(OS(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Product: CN(c1ccc(O)cc1)c1ccc2cc(Cl)cc(Cl)c2n1

Procedure:
4-[N-(6,8-dichloro-2-quinolinyl)-N-methylamino]-phenol was prepared from 2,6,8-trichloroquinoline and 4-(N-methylamino)phenol sulfate following essentially the same procedure as that described in Example 19, Part a). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.0-6.6 and 7.1 (9H, m, and d of d, quinoline, OH and phenyl protons; 3.6 (3H, s, N--CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]3[CH2:31][CH:26]4[CH2:27][N:28]([CH3:30])[CH2:29][CH:25]4[CH2:24]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.[C:40]1([CH2:46][C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:32][C:50]([NH:49][C:47](=[O:48])[CH2:46][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[S:51])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]3[CH2:24][CH:25]4[CH2:29][N:28]([CH3:30])[CH2:27][CH:26]4[CH2:31]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine (0.78 mg, 1.7 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (1.64 g, 9.2 mmol, 4.5 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was purified with a biotage system using an eluent EtOAc and 4% TEA (2 L) then EtOAc, 4% TEA, 1% MeOH (1 L). The solvent was removed to give 1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea (0.5 g, 50% yield). 1H NMR (400 MHz, DMSO): 8.48 (d, 1H), 7.92 (dd, 1H), 7.53 (s, 1H), 7.40 (m, 4H), 7.33 (d, 2H), 7.23 (m, 2H), 6.54 (d, 2H), 6.39 (d, 1H), 4.21 (d, 2H), 4.02 (s, 3H), 3.81 (m, 3H), 2.87 (d, 2H), 2.73 (m, 4H), 2.53 (m, 1H), 2.27 (m, 2H), 2.01 (s, 3H), 1.36 (m, 2H); MS (EI) for C34H35FN4O4S: 615 (M+H+).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][C:49](O)=[O:50])[CH:43]=1>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:50])[CH2:48][C:44]1[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=1)[CH2:19][CH2:18]2
Reactant: O=C(O)Cc1cccnc1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3cccnc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 3-pyridylacetic acid hydrochloride as the reacting carboxylic acid. LCMS: m/e 649.6 (M+H)+, 4.07 min (method 3). 1H NMR (599 MHz, <DMSO_CDCl3>) δ=8.49 (d, J=5.3 Hz, 2H), 7.88 (s, 2H), 7.33 (d, J=5.3 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.17 (s, 1H), 5.28 (d, J=5.3 Hz, 1H), 4.86-4.81 (m, 1H), 4.76 (s, 1H), 4.63 (br. s., 1H), 3.66 (d, J=12.9 Hz, 1H), 3.49 (d, J=12.9 Hz, 1H), 2.85-2.79 (m, 1H), 2.60-2.56 (m, 1H), 2.35-2.28 (m, 1H), 2.12 (dd, J=6.4, 17.0 Hz, 1H), 2.06 (t, J=11.1 Hz, 1H), 1.87-1.79 (m, 1H), 1.73 (br. s., 2H), 1.71 (s, 3H), 1.61-1.50 (m, 2H), 1.50-1.35 (m, 6H), 1.37-1.27 (m, 3H), 1.24 (d, J=9.4 Hz, 3H), 1.13-1.05 (m, J=12.9 Hz, 1H), 1.03-1.00 (m, 6H), 0.97 (s, 3H), 0.94 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][CH2:11][C:12](Br)=[O:13].C(N(CC)CC)C>C(Cl)Cl>[Br:10][CH2:11][C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1])=[O:13]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1ccc(Cl)cc1Cl
Yield: 80.4 %

Procedure:
This compound was prepared similarly to Example II-11 from 4.2 g of 2,4-dichloroaniline and 5.76 g of bromoacetyl bromide and 2.89 g of triethylamine in methylene chloride. This gave 5.9 g (80.4%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][CH:20]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:41]Br>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[C:23]4[CH:24]=[N:25][C:26]([NH2:40])=[C:27]([O:28][C@@H:29]([C:31]5[C:36]([Cl:37])=[CH:35][CH:34]=[C:33]([F:38])[C:32]=5[Cl:39])[CH3:30])[C:22]=4[O:21][C:20]=3[Br:41])[CH:16]=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrBr
Reactant: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: ClCCl
Product: C[C@@H](Oc1c(N)ncc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Br)oc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-{6-amino-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-furo[3,2-c]pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.68 mmol) in anhydrous DCM (10 mL) was added a solution of bromine (430 mg, 2.7 mmol) in DCM (3 mL). The resulting mixture was stirred at rt for 30 min. The mixture was quenched with sat. aq. Na2S2O3 (15 mL) and diluted with DCM (50 mL), then washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation afforded a yellow residue, which was purified by silica gel chromatography (Hex.-EtOAc=30:70→100% EtOAc) to give the title compound as a light-yellow solid. LC-MS (ES+): 668.01/669.99/671.97 [MH+]. 1H NMR (CDCl3, 400 MHz): δ 1.49 (s, 9H), 1.90 (d, J=6.8 Hz, 3H), 1.95-2.04 (m, 2H), 2.18-2.21 (m, 2H), 2.93 (m, 2H), 4.31-4.38 (m, 3H), 5.19 (br s, 2H), 6.54 (q, J=6.6 Hz, 1H), 7.08 (dd, J=8.8, 8.0 Hz, 1H), 7.30 (dd, J=8.8, 4.8 Hz, 1H), 7.85 (s, 1H), 7.94 (s, 1H), 8.05 (s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH:21]2[CH3:26])=[CH:5][C:6](=[O:18])[N:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)[CH:8]=1.Cl[C:28]1[N:33]=[CH:32][C:31]([CH:34]2[CH2:36][CH2:35]2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:2][C:3]1[C:4]([O:19][C@H:20]2[CH2:25][CH2:24][N:23]([C:28]3[N:33]=[CH:32][C:31]([CH:34]4[CH2:36][CH2:35]4)=[CH:30][N:29]=3)[CH2:22][C@H:21]2[CH3:26])=[CH:5][C:6](=[O:18])[N:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([F:17])[CH:10]=2)[CH:8]=1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: CC1CNCCC1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(c2ncc(C3CC3)cn2)CC[C@@H]1Oc1cc(=O)n(-c2ccc(C#N)c(F)c2)cc1Cl
Temperature: 100 °C
Yield: 5.3 %

Procedure:
A mixture of 4-(5-chloro-4-(3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile hydrochloride (159 mg, 0.399 mmol), 2-chloro-5-cyclopropylpyrimidine (67.9 mg, 0.439 mmol) and potassium carbonate (221 mg, 1.597 mmol) in DMSO (1.5 mL) was heated at 90-110° C. for 40 hrs and then additional potassium carbonate (110 mg, 0.788 mmol) was added. The resulting mixture was continuously heated at 100° C. overnight and then partitioned between EtOAc and water. The aqueous layer was extracted further with EtOAc (3×). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-100% EtOAc/hexane) to yield cis-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (10.2 mg, 5%, top spot on TLC plate) as a light yellow solid and to yield trans-4-(5-chloro-4-(1-(5-cyclopropylpyrimidin-2-yl)-3-methylpiperidin-4-yloxy)-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile (34.4 mg, 15%, bottom spot on TLC plate) as a light yellow solid. Cis-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.41 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.04 (s, 1H), 4.48-4.62 (m, 2H), 4.16 (td, J=8.80, 3.85 Hz, 1H), 3.19-3.29 (m, 1H), 2.98 (dd, J=13.75, 9.90 Hz, 1H), 2.18-2.30 (m, 1H), 2.01-2.12 (m, 1H), 1.63-1.77 (m, 2H), 1.08 (d, J=6.60 Hz, 3H), 0.89-0.95 (m, 2H), 0.57-0.62 (m, 2H). MS (ESI) 480 (M+H). Trans-isomers: 1H NMR (500 MHz, CDCl3) δ ppm 8.13 (s, 2H), 7.76 (t, J=7.42 Hz, 1H), 7.36-7.43 (m, 2H), 7.33 (d, J=8.25 Hz, 1H), 6.03 (s, 1H), 4.58 (app br s, 1H), 4.29-4.42 (m, 2H), 3.28-3.40 (m, 2H), 2.01-2.17 (m, 2H), 1.77-1.89 (m, 1H), 1.68-1.77 (m, 1H), 0.99-1.12 (m, 3H), 0.85-0.97 (m, 2H), 0.51-0.63 (m, 2H). MS (ESI) 480 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[N:10][C:9]2[C:4](=[CH:5][C:6]([N+:17]([O-])=O)=[C:7]3[N:15]=[N:14][N:13]([CH3:16])[C:8]3=2)[N:3]=1>Cl>[NH2:17][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[C:11]([OH:12])[C:2]([OH:1])=[N:3]2)=[C:8]2[N:13]([CH3:16])[N:14]=[N:15][C:7]=12
Reactant: Cn1nnc2c([N+](=O)[O-])cc3nc(O)c(O)nc3c21
Agent: Cl
Product: Cn1nnc2c(N)cc3nc(O)c(O)nc3c21
Reaction time: 1.5 h

Procedure:
A solution of stannous chloride dihydrate (2.26 g, 10 mmol) in 10 ml of conc. hydrochloric acid was added dropwise to a suspension of 7,8-dihydroxy-1-methyl-4-nitro-1H-1,2,3-triazolo[4,5-f]quinoxaline (0.79 g, 3 mmol) in 5 ml of conc. hydrochloric acid with stirring on an oil bath at 60°-70° C. Stirring was continued at this temperature for 90 min. Then the mixture was cooled on an ice bath, and filtered. The precipitate was washed with 1 ml of conc. hydrochloric acid, suspended in 150 ml of hot water, and adjusted to pH 6-7 with solid sodium hydrogen carbonate. After reflux for 1 h the mixture was cooled on ice and the crude product was isolated by filtration, dissolved in 40 ml of hot 2N sodium hydroxide and reprecipitated with 4M acetic acid giving 0.16 g (23%) of the pure amino compound; m.p.>300° C.; IR (KBr): 3435, 3350, 3240, 3100-2400, 1690, 1640 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[O:9][C:5]3[C:4]([C:18]([O:20][CH3:21])=[O:19])=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[N:7]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(F)cc2nc(-c3ccc(C)cc3)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(F)cc2nc(-c3ccc(CBr)cc3)oc12
Yield: 65.4 %

Procedure:
To methyl 5-fluoro-2-p-tolylbenzo[d]oxazole-7-carboxylate (420 mg, 1.47 mmol) in CCl4 (5 mL) was added NBS (262 mg, 1.47 mmol) and BPO (69 mg, 0.735 mmol), the resulting mixture was heated to reflux for 24 hr; then the solvent was evaporated and the residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=100:1-50:1) to obtain methyl 2-(4-(bromomethyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxylate as a white solid (350 mg, yield 65%). LC-MS (ESI) m/z 264 [M+1]+.
Reaction SMILES: Cl[C:2](=[CH2:11])[CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[OH-].[K+].C(O)(=O)C>CN(C)C=O>[CH2:3]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:11]
Reactant: C=C(Cl)CC1(O)CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C#CCC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10.00 Grams of the 1-(2'-chloroallyl)-1-cyclohexanol obtained above were dissolved in 94 g of N,N-dimethylformamide, and 9.65 g of potassium hydroxide in a flake form were added. The mixture was stirred at room temperature for 6 hours, and neutralized with a 20% acetic acid aqueous solution. The resultant mixture was subjected to extraction with toluene. The toluene phase was washed with water and dried over magnesium sulfate. The desiccant was filtered off and the toluene was distilled off under reduced pressure to give 7.68 g of 1-propargyl-1-cyclohexanol; m.p.=53°-54° C., FI-MS m/e 138(M+) (Propargyl compound/allene compound=100.0/0.0),
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(OCC)(=O)C.S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)=[CH:13][CH:14]=1)/[CH:6]=[CH:7]\[CH3:8]
Reactant: CC#CC(CC(=O)OC)c1ccc(OC2CCCCO2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: C/C=C\C(CC(=O)OC)c1ccc(OC2CCCCO2)cc1
Yield: 93.5 %

Procedure:
To a solution of 3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-ynoic acid methyl ester (4.07 g) obtained in Step 1 in ethyl acetate (70 mL) were added successively quinoline (1.52 mL) and 5% palladium-barium sulfate (0.4 g), followed by stirring the reaction mixture under normal pressure in an atmosphere of hydrogen at room temperature for 15.5 hours. Then, after the reaction mixture was filtered through Celite, water and 1N aqueous hydrochloric acid solution were added to the filtrate, followed by extraction with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid solution and saturated brine, dried and concentrated to give (Z)-3-[4-(tetrahydropyran-2-yloxy)-phenyl]-hex-4-enoic acid methyl ester (3.83 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#N)=[CH:18][CH:17]=1.C(O)=[O:25]>[Ni]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:25])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C#N)cc1
Reactant: O=CO
Agent: [Ni]
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1
Yield: 78.5 %

Procedure:
A mixture of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzonitrile (6.5 g), Raney nickel alloy (6.5 g) and 70% formic acid (100 ml) was heated under reflux for 2 hours. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The remaining oily material was chromatographed on a column of silica gel, and from the fractions eluted with chloroform-hexane (1:1, V/V), there were obtained crystlas (5.2 g, 78.5%) of 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde. Recrystallization from ether-hexane yielded colorless needles, m.p. 82°-84° C. Elemental analysis for C19H17NO3 ; Calcd.: C, 74.25; H, 5.57; N, 4.56. Found: C, 74.47; H, 5.53; N, 4.34.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[O:12][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(O)c(C)c([N+](=O)[O-])c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C)c([N+](=O)[O-])c1

Procedure:
A mixture of 433 g. 2,5-dimethyl-3-nitrophenol, 360 g. potassium carbonate, 326 ml. benzyl chloride and 2 liters dimethyl formamide is stirred overnight at 50° C. The reaction mixture is then filtered with suction and the filtrate is evaporated to dryness in a vacuum. The residue is poured on to 4 liters of ice-water and, after suction filtration and drying in the air, there are obtained 668 g. of yellowish crystals; m.p. 66°-68° C.