Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@@H:8]3[CH2:17][NH:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=1.C1C(=O)N([Br:27])C(=O)C1>OS(O)(=O)=O>[Br:27][C:5]1[C:6]2[CH2:7][C@@H:8]3[CH2:17][NH:16][CH2:15][CH2:14][N:9]3[C:10](=[O:13])[C:11]=2[CH:12]=[C:3]([C:2]([F:1])([F:18])[F:19])[CH:4]=1
Reactant: O=C1c2cc(C(F)(F)F)ccc2C[C@@H]2CNCCN12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: O=C1c2cc(C(F)(F)F)cc(Br)c2C[C@@H]2CNCCN12
Reaction time: 48 h
Yield: 25.5 %

Procedure:
A solution of (R)-8 trifluoromethyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (245 mg, 0.9 mmol) in H2SO4 (2 mL) was treated with NBS (210 mg, 1.17 mmol) at room temperature. After 48 h, the reaction mixture was quenched with saturated aqueous NaHCO3 and diluted with EtOAc (15 mL). The solution was extracted with EtOAc (50 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford a yellow oil. Purification of the oil by flash column chromatography (SiO2, 96:4:1 methylene chloride/methanol/triethylamine) provided (R)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one (80 mg, 25%) as an off-white solid. MS (ESI) 349 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[NH2:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)[CH3:20].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH:19]([C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([OH:27])[CH:26]=1)[CH3:20]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: COc1ccc(C(C)N)cc1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1O
Yield: 73 %

Procedure:
(4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (0.10 g, 0.35 mmol) and 5-(1-amino-ethyl)-2-methoxyphenol hydrochloride (excess) were coupled in N,N-dimethylformamide (2 mL) with triethylamine (0.15 mL). The solid material is collected by Buchner filtration, washed with diethyl ether and acetonitrile, and then dried under house vacuum to give (4Z)-6-bromo-4-({[1-(3-hydroxy-4-methoxyphenyl)ethyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione as a light tan powder (0.11 g, 73%).
Reaction SMILES: FC(F)(F)S(O[Si:7]([CH3:18])([CH3:17])[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16])(=O)=O.[CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[C-:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1.[Li+]>CCOCC>[CH3:17][Si:7]([CH3:18])([CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([C:22]2[CH:23]=[CH:24][C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]=2)=[CH:32]1)[CH:8]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH3:15])=[C:9]1[CH3:16]
Reactant: CC1=C(C)C([Si](C)(C)OS(=O)(=O)C(F)(F)F)C(C)=C1C
Reactant: c1ccc2cc(-[c-]3ccc4ccccc43)ccc2c1
Agent: [Li+]
Solvent: CCOCC
Product: CC1=C(C)C([Si](C)(C)C2C=C(c3ccc4ccccc4c3)c3ccccc32)C(C)=C1C
Reaction time: 19 h

Procedure:
To a solution of dimethyl(2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)silyl trifluoromethanesulfonate (Compound C, 7.50 g, 22.8 mmol, 1.00 eq.) in ether (25 mL) at −35° C. was added lithium (1-(2-naphthyl)indenide) (6.05 g, 24.4 mmol, 1.07 eq.). The reaction was stirred for 19 hours, and was then evaporated under vacuum. The residue was extracted with pentane (40 mL, then 2×20 mL) and the extract was filtered. The resulting solution was evaporated under vacuum to give a foam. The foam was extracted with pentane and the extracts were filtered to give a solution. The solution was evaporated under vacuum to give thick oil. Yield 9.44 g (98%). 1H NMR(C6D6): δ 8.20 (s, 1H), 7.84 (d, 1H), 7.76 (m, 2H), 7.70 (m, 2H) 7.51 (d, 1H), 7.27 (m, 4H), 6.71 (s, 1H), 3.75, (s, 1H), 2.94 (br s, 1H), 1.95 (s, 3H), 1.93 (s, 3H), 1.84 (s, 3H), 1.82 (s, 3H), −0.04 (s, 3H), −0.34 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]([O-])(=[O:17])C.[NH4+].C(O)=O>O>[CH:15]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:17]
Reactant: CCOC(=O)c1c(N)sc2c1CCC2
Reactant: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: CCOC(=O)c1c(NC=O)sc2c1CCC2
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of compound 2g [Compound of Formula 2 wherein R1=COOEt, R2, R3=(CH2)3] (10.0 g, 0.046 mol), ammonium acetate (3.64 g, 0.060 mol) and formic acid (35.74 mL, 0.946 mol) was stirred at 130-135° C. for 8 h. It was then cooled to room temperature and diluted with water (150 mL), extracted with ethyl acetate (3×100 mL), dried over Na2SO4, concentrated and purified by column chromatography to give pure compound of Formula (3g); 10.66 g; Yield: 97%; 1H NMR (200 MHz, CDCl3+DMSO-d6): δ 0.1.33 (t, J=8 Hz, 3H), 2.25-2.43 (m, 2H), 2.74-2.89 (m, 4H), 4.26 (q, J=8 Hz, 2H), 8.48 (s, 1H) 11.16 (bs, 1H).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([Cl:12])=[CH:7][C:8]=1[C:9]([NH2:11])=[O:10])[NH2:2].[N:13]([O-])=O.[Na+]>C(O)(=O)C.O>[Cl:12][C:6]1[CH:7]=[C:8]([C:9]([NH2:11])=[O:10])[C:3]2[N:4]([N:13]=[N:2][N:1]=2)[N:5]=1
Reactant: NNc1nnc(Cl)cc1C(N)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1cc(Cl)nn2nnnc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To an ice-cold solution of 3-hydrazino-4-aminocarbonyl-6-chloro-pyridazine (4.2 g; 0.0244 mole) [obtained as reported in J. Het. Chemistry, 7, 465 (1970)] in 15% acetic acid, a solution of sodium nitrite (1.55 g) in water (10 ml) was added dropwise. After stirring for one hour at 5°-10° C., the separated precipitate was filtered, crystallized from water, filtered again and dried under vacuum at 50° C. to give 3.44 g (77.5%) of the title compound, m.p. 226° C. (dec.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[I-:13].[Na+].C(Cl)(=O)C>C(#N)C>[I:13][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(-c2cccs2)ccn1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: Ic1cc(-c2cccs2)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 89.5 %

Procedure:
A 20 mL microwave vial was charged with 2-chloro-4-thiophen-2-yl-pyridine (428 mg, 2.19 mmol), sodium iodide (3.28 g, 21.9 mmol) and acetonitrile (3.5 mL). Acetyl chloride (0.24 mL, 3.4 mmol) was added and the vial was flushed with Argon and closed. The reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and quenched with 10 mL saturated Na2CO3 solution then extracted with 50 mL dichloromethane. The organic layer was washed with 10 mL 10% Na2S2O3 solution. The aqueous layers were extracted twice with 50 mL dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over 24 g SiO2 with EtOAc/hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to afford 563 mg (90%) of 2-iodo-4-thiophen-2-yl-pyridine as a light yellow solid.
Reaction SMILES: [I:1][C:2]1[C:3](O)=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cc(C(F)(F)F)ncc1I
Product: FC(F)(F)c1cc(Cl)c(I)cn1

Procedure:
A solution of 5-iodo-2-(trifluoromethyl)pyridin-4-ol (4.8 g, 16.6 mmol) in POCl3 (30 mL) was heated to 100° C. for 30 minutes. The resulting solution was concentrated under vacuum and the residue was neutralized by the addition of ice and aqueous potassium carbonate. The solution was extracted with ethyl acetate, dried (Na2SO4), filtered and concentrated under vacuum to give 4-chloro-5-iodo-2-(trifluoromethyl)pyridine. Retention time (min)=2.594, method [1], MS(ESI) 307.9 (M+H).
Reaction SMILES: F[C:2]1C=C(OC2N=CC=C3C=CN(C)C=23)C=CC=1N.[NH:20]1[C:24]2=[C:25]([O:29][C:30]3[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[S:38])=[CH:32][C:31]=3[F:49])[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[CH:21]1>>[F:49][C:31]1[CH:32]=[C:33]([NH:36][C:37]([NH:39][C:40](=[O:48])[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[S:38])[CH:34]=[CH:35][C:30]=1[O:29][C:25]1[N:26]=[CH:27][CH:28]=[C:23]2[CH:22]=[CH:21][N:20]([CH3:2])[C:24]=12
Reactant: Cn1ccc2ccnc(Oc3ccc(N)c(F)c3)c21
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Product: Cn1ccc2ccnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Yield: 87 %

Procedure:
Starting from the compound 265 and following the procedure described above for the synthesis of compound 262a (scheme 59, step 4, example 218), title compound 262b was obtained in 87% yield as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 12.40 (s, 1H), 11.78 (s, 1H), 7.83(dd, 1H, J1=10.95 Hz, J2=1.9 Hz), 7.56(d, 1H, 2.7 Hz), 7.49(d, 1H, J=5.5 Hz), 7.43-7.39 (m, 2H), 7.37-7.33 (m, 4H), 7.31-7.26 (m, 2H), 6.52(d, 1H, J2=2.9 Hz), 4.11 (s, 3H), 3.84 (s, 2H), MS (m/z): 435.1 (M+H) (found).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:21]=[CH:22][CH:23]=2)[CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[S:25]([CH3:24])(=[O:27])=[O:26])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(-c2cccc(CNCCc3cccnc3)c2)n1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)N(CCc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 18 was coupled with methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 403.
Reaction SMILES: [C:1]1(=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]#[N:32]>CC(C)=O>[C:1]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:30][C:31]#[N:32])=[CH:18][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: Oc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Yield: 13.1 %

Procedure:
The O-alkylation procedure described for 190 was followed. To stirred mixture of 4,4′-(cycloheptylidenemethanediyl)diphenol (189) (1.18 g, 4 mmol), K2CO3 (0.691 g, 5 mmol) and acetone (50 mL) was added bromoacetonitrile (0.418 mL, 6.0 mmol). The reaction mixture was refluxed for 3.5 h. Standard work-up and purification by silica gel chromatography afforded 0.175 g (13%) of compound 216 as a white solid and 0.700 g (47%) of the bis-alkylated material 2,2′-[(cycloheptylidenemethanediyl) bis(benzene-4,1-diyloxy)]diacetonitrile as a white solid. IR (film): 3413, 2921, 1605, 1504, 1210, 1170, 828, 729 cm−1. 1H NMR (300 MHz, CDCl3): δ 7.14 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.1 Hz, 2H), 5.0 (br, 1H), 4.74 (s, 2H), 2.33 (br s, 4H), 1.60 (s, 8H). LCMS (ESI): m/z 332 (M−H)−. Anal. Calcd for C22H23NO2, C, 79.25; H, 6.95; N, 4.20; Found: C, 79.14; H, 6.90; N, 4.21.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3[C:12]([C:13]=2[C:14]=1[F:15])=[CH:11][C:10]([CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=3.[Li][CH2:20][CH2:21][CH2:22][CH3:23].B(OC)(OC)[O:25]C>C1COCC1>[CH2:20]([O:25][C:3]1[C:2]([F:1])=[C:14]([F:15])[C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:11]=3)[CH2:6][C:5]=2[CH:4]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCc1ccc2c(c1)-c1c(ccc(F)c1F)C2
Reactant: [Li]CCCC
Reactant: COB(OC)OC
Solvent: C1CCOC1
Product: CCCCOc1cc2c(c(F)c1F)-c1cc(CCC)ccc1C2
Reaction time: 2 h

Procedure:
A solution of 5.2 g of 3,4-difluoro-6-propylfluorene (example 1) in 50 ml of dry THF is cooled to −70° C. and 15 ml of n-BuLi (1.6 m solution in hexane) are added dropwise under a protective gas atmosphere in such a way that the internal temperature is always below −70° C. Subsequently, the mixture is stirred at this temperature for a further 2 h and then 2.7 g of trimethyl borate dissolved in 10 ml of THF are added at the same temperature. The reaction mixture is allowed to come to −10° C., quenched with water and acidified with hydrochloric acid. After extraction with MTBE, the combined organic phases are washed with saturated NaCl solution and dried over sodium sulfate. The crude boronic acid obtained after the removal of the solvent is dissolved in 100 ml of MTBE, heated to boiling, admixed rapidly with 7.5 ml of 35 percent aqueous hydrogen peroxide solution and stirred under reflux for a further 2.5 h. After cooling, the phases are separated, the aqueous phase is extracted once more with MTBE and the combined organic phases are washed successively with water, saturated sodium sulfite solution and saturated NaCl solution. After drying over sodium sulfate and removal of the solvent under reduced pressure, the crude product is purified by column chromatography on silica gel using 9:1 (v/v) heptane/ethyl acetate as the eluent. The resulting 3,4-difluoro-6-propylfluoren-2-ol is heated to boiling with 2.4 g of 1-bromobutane and 5.4 g of potassium carbonate in 120 ml of MEK for 6 h. After cooling, the reaction mixture is added to ice/water and extracted with MTBE, and the organic phases are washed with water and saturated NaCl solution and dried over sodium sulfate. After the solvents have been removed under reduced pressure, the colorless crude product is purified chromatographically on silica gel with 2:8 (v/v) dichloromethane/heptane as the eluent and recrystallized from heptane. 2.7 g of 2-butyloxy-3,4-difluoro-6-propylfluorene are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[N:14]2[CH3:23])[CH2:10][CH2:11][N:35]2[CH2:36][CH2:37][CH:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[O:25][CH3:24])[CH2:33][CH2:34]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C(=O)c2ccccc2C1C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccccc1C1CCNCC1
Product: COc1ccccc1C1CCN(CCC(c2ccc(Cl)c(Cl)c2)C2c3ccccc3C(=O)N2C)CC1
Product: Cl
Yield: 158.5 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.368 g) was coupled to 4-(2-methoxyphenyl)piperidine (0.203 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in Example 8 to afford the desired title compound (0.469 g); mp 175°-182° C.; MS: m/z=523(M+1); NMR(CD3SOCD3): 1.83-1.90 (m,3), 2.05-2.13 (m,2), 2.80 m(1), 3.07 (s,3), 3.57 (m,2), 3.8 (s,3), 4.89 (d,1, J=3.7), 6.7 (dd,1, J=8.4, 2), 7.0 (m,3), 7.12-7.6 (m,6), 7.94 (d,1, J=7.5). Analysis for C30H32Cl2N2O2.1.0 HCl.1.5 H2O: Calculated: C, 61.39; H, 6.18, N, 4.77; Found: C, 61.33; H, 6.12; N, 4.99.
Reaction SMILES: C(OC1C=CC(C(Cl)=O)=CC=1)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[NH2:17].[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37]>C1(C)C=CC=CC=1.C(O)C>[CH2:36]([O:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([N:47]=[C:48]=[S:49])=[O:46])=[CH:41][CH:40]=1)[CH3:37].[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:48]([NH:47][C:45](=[O:46])[C:42]2[CH:43]=[CH:44][C:39]([O:38][CH2:36][CH3:37])=[CH:40][CH:41]=2)=[S:49])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: CCOc1ccc(C(=O)Cl)cc1
Agent: CCOc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4-Ethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-ethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-ethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (72 mg, yield 89%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:12][C:13](=[N:14]O)[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[CH2:1]([C:5]1[N:9]2[CH:10]([C:16]3[CH:17]=[CH:18][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][N:31]=[N:30][N:29]=4)=[CH:20][CH:21]=3)[CH2:11][CH2:12][CH:13]([NH2:14])[C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=NO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2N

Procedure:
Alternatively, the title compound of Example 1451 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1449) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1451.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3].[CH:13]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)=[CH2:14].C(N(CC)CC)C>CO>[CH2:1]([O:4][C:5]1[C:6](=[O:12])[C:7]2[C:8](=[CH:14][CH:13]=[C:15]3[C:16]=2[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CC1=CCCCC1
Reactant: C=CCOC1=CC(=O)C=CC1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
2-Allyloxy-1,4-benzoquinone (10.0 g, 60.9 mM) and 1-Vinylcyclohexene (19.8 g, 183 mM) were dissolved in 100 ml of MeOH, and refluxed for 3 hours. The reaction solution was cooled to room temperature, and then Triethylamine (5 ml) and NaIO4 (13.0 g, 61.0 mM) were added thereto, and stirred vigorously for another 1 hours. Reaction solution therein was filtered and the filtrate was concentrated by distillation under reduced pressure and was then purified by chromatography on silica gel to give 7.6 g (28.4 mM) of 3-Allyloxy-5,6,7,8-tetrahydro-1,4-phenanthrenequinone.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])=[C:4]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:31][N:32]1[C:36]([S:37](Cl)(=[O:39])=[O:38])=[CH:35][CH:34]=[N:33]1.[Cl:41]CCl>O>[Cl:41][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:14]([C:4]2[CH:3]=[CH:2][CH:13]=[CH:12][C:5]=2[C:6]([NH:8][CH:9]([CH3:11])[CH3:10])=[O:7])[S:37]([C:36]2[N:32]([CH3:31])[N:33]=[CH:34][CH:35]=2)(=[O:39])=[O:38])=[CH:17][CH:18]=1
Reactant: Cn1nccc1S(=O)(=O)Cl
Reactant: CC(C)NC(=O)c1ccc(Cl)cc1NCc1ccccc1
Reactant: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccccc1N(Cc1ccc(Cl)cc1)S(=O)(=O)c1ccnn1C

Procedure:
3-(4-Chloro-benzylamino-N-isopropyl-benzamide (30 mg, 0.1 mmol), diisopropylethylamine (35 μL, 0.2 mmol) and 1-methyl-1H-pyrazole-5-sulfonyl chloride (36 mg, 0.2 mmol) were stirred in dry dichloromethane (2 ml) at room temperature for 72 hrs. The reaction was diluted with dichloromethane (5 ml) and water (5 ml) with stirring. The organics were collected, dried (PTFE frit) and concentrated in vacuo. The residue was purified by preparative TLC (10% ethyl acetate/dichloromethane) to yield the product as an off-white solid (11.9 mg). HPLC retention time 8.04 min. Mass spectrum (ES+) m/z 44 (M+H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:7])=[CH:5][N:6]=1.[C:8]12([C:18](Cl)=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1COCC1.C(OCC)(=O)C>[Cl:7][C:4]1[S:3][C:2]([NH:1][C:18]([C:8]23[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]2)[CH2:9]3)=[O:19])=[N:6][CH:5]=1
Reactant: Nc1ncc(Cl)s1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ncc(Cl)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C
Reaction time: 48 h
Yield: 51.3 %

Procedure:
A mixture of 2-amino-5-chlorothiazole (2.00 g, 14.9 mmol), 1-adamantanecarbonyl chloride (3.54 g, 17.8 mmol), 4-dimethylaminopyridine (1.10 g, 0.90 mmol) and triethylamine (4.15 mL, 23.0 mmol) in 80 mL of THF was stirred at 80° C. for 48 hours The mixture was cooled to ambient temperature, diluted with 100 mL of ethyl acetate and washed with brine. The layers were separated and the aqueous phase was extracted twice with 50 mL of ethyl acetate. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, dichloromethane) afforded 2.27 g of the title compound: MS (DCI/NH3) m/z 297 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11](=[CH2:27])[CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[O:4][CH2:3][CH2:2]1>CO>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH:11]([CH3:27])[CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[O:4][CH2:3][CH2:2]1
Reactant: C=C(CNc1cc(-c2ccc(C)nc2)ncn1)c1ccnc2c1OCCO2
Solvent: CO
Product: Cc1ccc(-c2cc(NCC(C)c3ccnc4c3OCCO4)ncn2)cn1
Reaction time: 2 h

Procedure:
As shown in step 8-ii of Scheme 8, N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)allyl]-6-(6-methyl-3-pyridyl)pyrimidin-4-amine (150 mg, 0.4151 mmol) was dissolved in MeOH and the reaction mixture was placed under an atmosphere of H2. After stirring for 2 hours, the mixture was filtered, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0-5% MeOH/DCM) to produce N-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine (Compound 1029): LCMS=364.39 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.00 (d, J=2.0 Hz, 1H), 8.63 (s, 1H), 8.20 (dd, J=8.1, 2.3 Hz, 1H), 7.81 (d, J=5.0 Hz, 1H), 7.27 (d, J=4.2 Hz, 1H), 6.82 (d, J=5.1 Hz, 1H), 6.71 (s, 1H), 4.43 (dd, J=5.1, 3.0 Hz, 2H), 4.27 (dd, J=5.1, 3.0 Hz, 2H), 3.56 (m, 3H), 2.62 (s, 3H), 1.32 (d, 3H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.[H-].[Na+].I[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[CH:24]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h

Procedure:
2-chloro-6-(4-methoxybenzylamino) purine was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine.