Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14](OCC)=[O:15])=[C:10]([OH:19])[C:9]3[CH2:20][O:21][CH2:22][C:8]2=3)=[CH:4][CH:3]=1.C([NH:29][CH2:30][C:31]([OH:33])=[O:32])(C)(C)C.C(Cl)Cl>COCCOC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([NH:29][CH2:30][C:31]([O:33][CH2:24][CH2:2][CH2:3][CH3:4])=[O:32])=[O:15])=[C:10]([OH:19])[C:9]3[CH2:20][O:21][CH2:22][C:8]2=3)=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Reactant: CC(C)(C)NCC(=O)O
Solvent: COCCOC
Solvent: ClCCl
Product: CCCCOC(=O)CNC(=O)c1c(O)c2c(n(Cc3ccc(Br)cc3)c1=O)COC2
Temperature: 120 °C

Procedure:
To a solution of the ester from Step C (563 mg, 1.43 mmol) in 1,2-dimethoxyethane (12 mL) was added tert-butyl glycine (0.390 mL, 2.86 mmol). The mixture was heated in the microwave at 120° C. for 1.5 h. The mixture was concentrated in vacuo to give a yellow oil which was taken up in the minimum amount of CH2Cl2 and chromatographed on a Biotage 40S+ column with a 10, 20, 30, EtOAc/hexanes gradient elution to give compound, 28-4, as a white solid, 494 mg: 1H NMR (500 MHz, CDCl3): δ 1.49 (s, 9 H), 4.09 (d, 2 H, J=5.2 Hz), 4.91 (t, 2 H, J=3.2 Hz), 5.01 (s, 2 H), 5.05 (t, 2 H, J=3.2 Hz), 7.09 (d, 2 H, 8.3 Hz), 7.46 (d, 2 H, J=8.2 Hz), 10.44 (m, 1 H); HPLC/MS: 1.28 min, 480.0 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:2]=1.[OH-].[Na+].O.NN>C(O)COCCO>[C:11]1([CH2:10][CH2:9][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(CCc1ccccc1)c1cccnc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: c1ccc(CCCc2cccnc2)cc1

Procedure:
Heat a mixture of 2-phenylethyl 3-pyridinyl ketone (19.5 g, 0.092M), NaOH (8.0 g), hydrazine hydrate (8 ml, 85% in H2O) and diethylene glycol (125 ml) to 240° C. for 4 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1.[CH3:21][NH2:22].[I-].[Na+]>C(#N)C.O>[CH3:21][NH:22][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:20])[C:8]=2[CH:7]=1
Reactant: CN
Reactant: O=c1c2ccccc2sc2ccc(OCCCCl)cc12
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CNCCCOc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
26 g (85 mmol) 2-(3-chloropropoxy)-9H-thioxanthen-9-one is suspended in 140 mL acetonitrile. 66 g (73.2 mL, 0.85 mol) of a 40% solution of methyl amine in water was added and the mixture was heated to 60° C. After four hours, 1.3 g (8.5 mmol) sodium iodide and 20 mL of a 40% solution of methyl amine in water were added and the reaction was allowed to continue for 16 hours at 60° C. The precipitated compounds were isolated by filtration and washed three times with 100 mL acetonitrile. The pooled acetonitrile fractions were evaporated under reduced pressure. The crude 2-(3-methylaminopropoxy)thioxanthen-9-one was crystallized from 200 mL hexane, isolated by filtration and dried. 19 g of 2-(3-methylaminopropoxy)thioxanthen-9-one was isolated. 2-(3-methylaminopropoxy)thioxanthen-9-one was further purified by preparative column chromatography on a Prochrom LC80 column, using Kromasil C18 100A 10 mm as silica and methanol/1M ammonium acetate 68/32 as eluent at a flow rate of 150 mL per minute.
Reaction SMILES: Br[CH2:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C:5](=[O:13])[O:4]1.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([OH:34])[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1>>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Cl:36])[C:20]=1[NH:21][C:22]1[C:31]2[C:26](=[C:27]([O:34][CH2:2][C@H:3]3[C@H:7]4[C@H:6]([O:10][C:9]([CH3:12])([CH3:11])[O:8]4)[C:5](=[O:13])[O:4]3)[C:28]([O:32][CH3:33])=[CH:29][CH:30]=2)[O:25][C:24](=[O:35])[CH:23]=1
Reactant: CC1(C)O[C@H]2[C@H](CBr)OC(=O)[C@H]2O1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OC[C@@H]1OC(=O)[C@H]2OC(C)(C)O[C@@H]12

Procedure:
The title compound was prepared from (3aS,6R,6aR)-6-(bromomethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4-(3aH)-one and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.57 (s, 1H), 8.83 (s, 2H), 7.98 (d, 1H), 7.23 (s, 1H), 5.16 (m, 2H), 4.87 (m, 1H), 4.67 (s, 1H) 4.36 (m, 2H), 3.93 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H); MS (ESI): 522.8.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[CH2:31].Br[C:39]1[CH:40]=[CH:41][C:42]2[C:43]3[N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:51]([CH2:58][O:59][CH2:60][CH3:61])=[N:50][C:44]=3[C:45]([NH2:49])=[N:46][C:47]=2[CH:48]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:60]([O:59][CH2:58][C:51]1[N:52]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:43]2[C:42]3[CH:41]=[CH:40][C:39](/[CH:31]=[CH:30]/[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)=[CH:48][C:47]=3[N:46]=[C:45]([NH2:49])[C:44]=2[N:50]=1)[CH3:61]
Reactant: C=Cc1ccccn1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCc1nc2c(N)nc3cc(/C=C/c4ccccn4)ccc3c2n1CCCOC
Temperature: 120 °C

Procedure:
A thick walled glass tube, equipped with magnetic stir-bar, was charged with toluene (20 mL/g), palladium (II) acetate (0.1 equivalents), tri-ortho-tolylphosphine (0.3 equivalents), triethylamine (3.0 equivalents), 2-vinylpyridine (1.0 equivalent), and 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 eq.). The tube was purged with nitrogen and sealed. The reaction mixture was heated at 120° C. for 24-48 hours. The reaction mixture was allowed to cool and then concentrated under reduced pressure. The solid residue was partitioned between dichloromethane and water, and the mixture was adjusted to pH 12 with the addition of 10% aqueous sodium hydroxide. The organic layer was separated and purified by flash chromatography on silica gel (eluting with chloroform:methanol in a gradient from 100:0 to 90:10) followed by recrystallization from acetonitrile to provide (E)-2-ethoxymethyl-1-(3-methoxypropyl)-7-(2-pyridin-2-ylvinyl)-1H-imidazo[4,5-c]quinolin-4-amine as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29]N)[C:24]=2[F:31])=[CH:19][CH:18]=1)[CH2:14][CH2:15][CH3:16]>>[CH2:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]3[C:6]4[CH2:5][C:4]5[C:8](=[CH:9][CH:10]=[C:2]([NH2:1])[CH:3]=5)[C:7]=4[NH:29][C:25]=3[C:24]=2[F:31])=[CH:21][CH:22]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccc(-c2cccc(NN)c2F)cc1
Reactant: Nc1ccc2c(c1)CCC2=O
Agent: Cl
Product: CCCCc1ccc(-c2ccc3c4c([nH]c3c2F)-c2ccc(N)cc2C4)cc1
Yield: 17 %

Procedure:
The title material is prepared in 17% yield by reacting 5-Amino-indan-1-one (commercially available) and (4′-Butyl-2-fluoro-biphenyl-3-yl)-hydrazine hydrochloride (Example 78, step) in an analogous manner to example 1, step 3; LC/MS calculated for [M+H]+ C25H23FN2: 371.2, found: 371.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH3:27])[CH:22]=3)[CH:17]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:10]=2)[CH:8]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)c(-c2cccc(OCCN3CCCCC3)c2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
Synthesized from 2-(3′-benzyloxy-5-methoxybiphenyl-2-yl)-6-methoxynaphthalene (205 mg) according to an analogous synthetic method to Example 22, 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (176 mg) was obtained. To a solution of 5′-methoxy-2′-(6-methoxynaphthalen-2-yl)biphenyl-3-ol (276 mg) in N,N-dimethylformamide (7 ml) were sequentially added potassium carbonate (220 mg) and 1-(2-chloroethyl)piperidine (280 mg), and the solution was stirred for 2 hours at 60° C. Water was added thereto followed by stirring, the solution was extracted with ethyl acetate, then sequentially washed with water and brine, and the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (319 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][C:9]([NH2:12])=[N:10][N:11]=1.[C:13]1([CH:19]([C:25](OCC)=[O:26])[C:20](OCC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>O>[C:13]1([C:19]2[C:20]([OH:21])=[N:12][C:9]3[N:10]([N:11]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[N:8]=3)[C:25]=2[OH:26])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nnc(-c2ccccn2)[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Solvent: CCCCN(CCCC)CCCC
Solvent: O
Product: Oc1nc2nc(-c3ccccn3)nn2c(O)c1-c1ccccc1
Temperature: 180 °C
Yield: 50 %

Procedure:
20 g (124.1 mmol) 5-Pyridine-2-yl-4H-[1,2,4]triazole-3-ylamine and 52.8 g (223.4 mmol) diethyl phenylmalonate are heated in 48.8 mL (204.8 mmol) tributylamine at 180° C. over night. After addition of additional 27 mL diethyl phenylmalonate the reaction mixture is heated for another night at 180° C. The reaction mixture is diluted with water and 2N NAOH and extracted three times with methyl-tert.butylether. The organic extracts are discarded after TLC check. The aqueous phase is acidified with 2M HCl until a pH of 1. The formed precipitate is collected by filtration, washed with plenty of water and dried. 18.96 g (45%) of the desired product are obtained which are used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[NH3:22].CO>ClCCl>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH2:22])=[C:4]([F:21])[C:5]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: N
Reactant: Fc1c(CBr)ccc(Cl)c1Oc1cccc2ccccc12
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}naphthalene (0.96 g, 2.63 mmol) in dichloromethane (10 mL) was added 7N ammonia in methanol (20 mL, 140 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with dichloromethane to give the desired product (0.769 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.29-8.37 (m, 1H), 7.94-8.03 (m, 1H), 7.60-7.71 (m, 4H), 7.56 (t, 1H), 7.36 (t, 1H), 6.56 (d, 1H), 4.13 (s, 2H). ES MS: m/z 302 (M+1).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:20][C:22]2[C:31]3[C:26](=[CH:27][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12]
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3cc(C(F)(F)F)ccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 75.4 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloro-7-trifluoromethylquinoline (162 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (72 mg, yield 75%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH:15]=2)[C:10]([Br:27])=[N:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:20]([O:19][C:17]([C:14]1[CH:15]=[C:16]2[C:11]([C:10]([Br:27])=[N:9][NH:8]2)=[CH:12][CH:13]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(Br)c2ccc(C(=O)OCc3ccccc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)c1ccc2c(Br)n[nH]c2c1

Procedure:
A solution of 3-bromo-indazole-1,6-dicarboxylic acid 6-benzyl ester 1-tert-butyl ester (2.05 g, 4.75 mmol) and TFA (3.66 mL, 47.5 mmol) in CH2Cl2 (30 mL) was stirred at RT for 16 h. A saturated aqueous solution of NaHCO3 was added, the layers were separated and the aqueous layer was extracted with CH2Cl2 (×3). The combined organic extracts were dried (Na2SO4), filtered and concentrated and the material thus obtained was used without further purification in the next step. MS (UPLC/MS): 331.2/333.2 [M+H]+, 329.3/331.2 [M−H]−; tR (UPLC conditions m): 1.18 min.
Reaction SMILES: CC(C)N=C=NC(C)C.F[C@H]([C@@H](F)CCCCC)CO[C:14]1[CH:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][Si:31]([CH3:54])([CH3:53])[CH2:32][CH2:33][C:34]([F:52])([F:51])[C:35]([F:50])([F:49])[C:36]([F:48])([F:47])[C:37]([F:46])([F:45])[C:38]([F:44])([F:43])[C:39]([F:42])([F:41])[F:40])=[CH:22][CH:21]=2)=[N:18][CH:19]=1.[CH2:62]([C@H:67]1[CH2:72][CH2:71][C@H:70]([C:73]([OH:75])=[O:74])[CH2:69][CH2:68]1)[CH2:63][CH2:64][CH2:65][CH3:66]>C(OCC)(=O)C.CN(C1C=CN=CC=1)C>[CH3:54][Si:31]([CH3:53])([CH2:32][CH2:33][C:34]([F:52])([F:51])[C:35]([F:49])([F:50])[C:36]([F:47])([F:48])[C:37]([F:45])([F:46])[C:38]([F:43])([F:44])[C:39]([F:40])([F:41])[F:42])[CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[N:16]=[CH:15][C:14]([O:74][C:73]([C@H:70]3[CH2:69][CH2:68][C@H:67]([CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:72][CH2:71]3)=[O:75])=[CH:19][N:18]=2)=[CH:21][CH:22]=1
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCCCC[C@H](F)[C@@H](F)COc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCC[C@H]1CC[C@H](C(=O)Oc2cnc(-c3ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of DIC (0.061 g, 0.48 mmol) in ethyl acetate (3.0 ml) was added dropwise to a stirred solution of compound 48 (0.261 g, 0.400 mmol), trans-4-pentylcyclohexanecarboxlic acid (0.095 g, 0.480 mmol) and DMAP (4.90 mg, 0.04 mmol) in ethyl acetate (3.0 ml). The reaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel, eluted with hexane/ethyl acetate (4:1)] to give a colorless solid, which recrystallized acetonitrile to yield colorless crystals.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]2[NH:21][CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]2[N:21]([C:3](=[O:4])[CH2:2][Cl:1])[CH2:20][CH2:19][NH:18][C:17]2=[O:22])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C2NCCNC2=O)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C2C(=O)NCCN2C(=O)CCl)cc1OC
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: a solution of 11.5 g (0.1 mol) of chloroacetyl chloride in 50 ml of chloroform is added, while cooling, to 23.6 g (0.1 mol) of 3-(3,4-dimethoxyphenyl)-piperazin-2-one (Example 1), 150 ml of chloroform and 10.1 g of triethylamine. The mixture is stirred for a further hour at room temperature and is concentrated in vacuo, the residue is taken up in aqueous potassium carbonate solution, and the solution is extracted by shaking with ethyl acetate. Distilling off the ethyl acetate gives 17.5 g≈56% of theory of 3-(3,4-dimethoxyphenyl)-4-chloroacetylpiperazin-2-one.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O.C(=O)(O)[O-:28].[Na+].I([O-])(=O)(=O)=O.[Na+]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[Si:1]([O:8][CH:9]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[O:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc2ccccc2c1
Reactant: O=C([O-])O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC(CCCCC=O)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of alkene 182 (1.05 g, 3.23 mmol) in t-butyl alcohol (50 mL) were successively added water (10 mL), solid sodium bicarbonate (2.71 g, 32.3 mmol), sodium periodate (4.15 g, 19.38 mmol), and osmium tetroxide (8 mg, 0.032 mmol). The mixture turned light brown and a precipitate formed in large amount, making magnetic stirring impossible so the mixture was shaken by hand every 10 minutes for 3.5 hours and the brownish color almost disappeared. The reaction was quenched with a 10% aqueous solution of sodium thiosulfate. After 30 minutes, the white precipitate was filtered off and rinsed with diethyl ether. The filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether and water. The aqueous layer was extracted (2×50 mL) with diethyl ether. The combined organic layers were washed successively with a 10% aqueous solution of sodium thiosulfate, water and brine, dried (MgSO4), and concentrated in vacuo, yielding the title compound 183 as a crude oil in 91% yield (1.05 g). 1H NMR: (300 MHz, CDCl3) δ: 9.73 (t, J=1.9 Hz, 1H), 7.83-7.78 (m, 3H), 7.69 (s, 1H), 7.49-7.43 (m, 3H), 4.80 (t, J=6.9 Hz, 1H), 2.39 (td, J=7.1, 1.6 Hz, 2H), 1.81-1.55 (m, 4H), 1.43-1.25 (m, 2H) 0.90 (s, 9H), 0.04 (s, 3H), −0.15 (s, 3H). MS (ESI) 225 (M+1-TBSO).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=1[CH3:17])[CH3:13]
Reactant: CCOC(=O)C1(CC)CCCC1O
Reactant: Cc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1(CC)CCCC1OC(=O)c1ccccc1C
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-ethyl-cyclopentane carboxylate (4.90 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.22 ml) was slowly added, then 2-methyl-benzoyl chloride (5.28 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 8.99 g of yellow liquid. MS: m/e 304(M+″), 261, 244, 139, 119(base), 91.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=O)[C:4]=2[CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C(#N)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:12]=[N:11][C:10]2[O:9][CH:8]([CH2:13][CH2:14][Cl:15])[CH2:7][N:6]([CH3:16])[C:5](=[S:19])[C:4]=2[CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CN1CC(CCCl)Oc2ncc(Br)cc2C1=O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CN1CC(CCCl)Oc2ncc(Br)cc2C1=S
Yield: 59.6 %

Procedure:
To a solution of 5.9 g (0.016 mole) of 7-bromo-2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5(4H)-one in 25 ml of acetonitrile was added 2.07 g (0.005 mole) of phosphorus pentasulfide. The mixture was heated to reflux for 3 hr. The reaction mixture was diluted with 100 ml of toluene and filtered. The filtrate was washed with 3×50 ml of saturated sodium bicarbonate and 50 ml of water, dried over sodium sulfate, filtered, and concentrated by rotary evaporation to ~5-10 ml. Crystallization ensued and 3.0 g of crystals were collected. The mother liquor was concentrated giving 1.0 g additional crystals. The two crops were combined and recrystallized from diisopropylether/toluene to give ~3 g (56%) of yellow crystals, m.p. 138°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].CN([CH:16]=[O:17])C>>[Cl:1][C:2]1[CH:7]=[C:6]([O:17][CH3:16])[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CN(C)C=O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1C
Reaction time: 6 h

Procedure:
A solution of 2-chloro-4-floro-5-methylnitrobenzene (1 mmole) in DMF (5 mL) was treated with fresh sodium methoxy (1.1 mmole), and the mixture was stirred for 6 h. Evaporation and chromatography gave 2-chloro-4-methoxy-5-methylnitrobenzene.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](I)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:25].C[Si](C)(C)[O:31][CH2:32][C:33]#[CH:34].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:34]#[C:33][CH2:32][OH:31])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:9][C:8]=1[Cl:25]
Reactant: C#CCO[Si](C)(C)C
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OCC#Cc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (1.52 g), trimethyl(prop-2-ynyloxy)silane (0.7 mL), triethyl amine (0.5 mL) in DMF (10 mL) was added Pd(PPh3)2Cl2 (106 mg), CuI (114 mg) and the mixture was heated at 40° C. overnight. The solvent was removed, then methanol (10 mL) and 4N HCl (2 mL) were added. The reaction mixture was stirred at room temperature for one hour and the solvent was removed. Another 10 mL methanol and triethyl amine (2 mL) were added and the reaction mixture was stirred at room temperature for one hour. The solvent was removed and the residue was purified by flash chromatography, eluting with EtOAc to give the desired product. LCMS ESI(+) m/z: 434 (M+1). Yield: 86%.