Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([OH:12])[N:3]=1.P(Cl)(Cl)(Cl)=O.[CH3:18][O-].[Na+]>[Cl-].[NH4+]>[CH3:18][O:12][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=1
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(C)c([N+](=O)[O-])c(C)n1
Temperature: 100 °C
Reaction time: 1.33 h

Procedure:
4,6-Dimethyl-5-nitropyrimidin-2-ol (18.4 g, 108 mmol) wad added portionwise to a stirred phosphoryl chloride (3.0 mL) at 0° C., and the mixture was stirred at 100° C. for 80 min. The mixture was concentrated in vacuo, and methanol (180 mL) was added to the residue carefully at 0° C. Sodium methoxide (28% solution in methanol, 68.8 g, 357 mmol) was added dropwise to a stirred mixture at 0° C., and the mixture was stirred at 0° C. for 10 min. The mixture was diluted with aqueous saturated ammonium chloride and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow wax (13.0 g, 71.0 mmol, 66%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([NH:10][NH2:11])=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH3:13][NH:14][C:15](=NC)[CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[N:14]([CH3:13])[C:15]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])=[N:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: C=CCCCC(=NC)NC
Reactant: Cc1nc(C)c(C(=O)NN)s1
Agent: Cl
Product: C=CCCCc1nnc(-c2sc(C)nc2C)n1C

Procedure:
The title compound was prepared in analogy to Preparation 11 in 0.17 g yield starting from 2,4-dimethyl-1,3-thiazole-5-carbohydrazide (0.50 g) and N,N′-dimethyl-5-hexenimidamide hydrochloride (0.51 g). MS (m/z): 263 [MH]+.
Reaction SMILES: CN1CCOCC1.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11].[NH:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18](ON1C(=O)CCC1=O)=[O:19]>CN(C=O)C>[NH:16]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:17][C:18]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O

Procedure:
1.4 ml (11 mmol) of N-methylmorpholine are added to 1.15 g (10 mmol) of proline in 50 ml of DMF. The mixture is cooled with an ice bath, 3.06 g (10 mmol) of Boc-Gly-OSu are then added and the pH is adjusted to between 6 and 7 throughout the reaction (14 h) by successive additions of small amounts of N-methylmorpholine (this substance is used as a proton acceptor). The DMF is evaporated off and the evaporation residue is taken up with AcOEt; after precipitation in petroleum ether and then filtration, the expected product is collected.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH2:18])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].O>N1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:19][C:13]3[CH:14]=[N:15][C:16]([NH:18][C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=4)=[O:28])=[CH:17][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccn1
Reactant: Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2nc(-c3ccc([N+](=O)[O-])cc3)[nH]c2cn1)c1ccccn1
Yield: 31.6 %

Procedure:
A solution of amine 8 (0.145 g, 0.57 mmol) and picolinoyl chloride hydrochloride (0.180 g, 1.01 mmol) in dry pyridine (5 ml) was stirred at room temperature overnight. After addition of water the brown solid was filtered and passed through a SiO2 gel, eluting with CH2Cl2: MeOH (100:5) affording the desired product 21 (0.065 g, 31%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:12][C:13]([C:15]1[N:16]=[C:17]([N:20]2[CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]2)[S:18][CH:19]=1)=[O:14])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>CN(C)C=O>[C:29]([S:31][CH:22]1[CH2:21][N:20]([C:17]2[S:18][CH:19]=[C:15]([C:13](=[O:14])[NH:12][C@@H:10]([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:2])[CH3:3])[N:16]=2)[CH2:23]1)(=[O:32])[CH3:30]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@@H](C)CO[Si](C)(C)C(C)(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.16 g, 2.50 mmol) (obtained as described in Reference Example 35(5)) in dimethylformamide (60 ml) was added potassium thioacetate (1.71 mg, 15.0 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (4:1→2:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-2-(t-butyldimethylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (709 mg, yield 60%) as a pale brown oil.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][CH2:5][O:6][C:7](=[C:15]1[CH:22]2[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:24][CH:16]1[CH2:17]3)[CH2:21]2)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[CH:9]=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[OH:14][C:10]1[CH:9]=[C:8]([C:7](=[C:15]2[CH:22]3[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:24][CH:16]2[CH2:17]4)[CH2:21]3)[O:6][CH2:5][CH2:4][I:1])[CH:13]=[CH:12][CH:11]=1
Reactant: [I-]
Reactant: Oc1cccc(C(OCCCl)=C2C3CC4CC(C3)CC2C4)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: Oc1cccc(C(OCCI)=C2C3CC4CC(C3)CC2C4)c1
Yield: 102.9 %

Procedure:
Sodium iodide (14.0 g, 0.09 mol) and [(2-chloroethoxy)(3-hydroxyphenyl)methylene]adamantane (3.0 g, 0.009 mol) were dissolved in dry acetone and refluxed for 6 days. The reaction was followed by TLC analysis (silica gel, 10% ethyl acetate/hexane) and after the completion of reaction, solvent was evaporated to obtain a white solid. This solid was washed with methylene chloride several times and the combined organic layers were again washed with water. The organic layer was dried over MgSO4 and concentrated to give 3.8 g (100%) of product as an oily material: 1H NMR (CDCl3) δ 1.78-1.97 (m, 12H), 2.64 (bs, 1H), 3.19 (t, 2H, J=7.1 MHz), 3.35 (bs, 1H), 3.69 (t, 2H, J=7.1 MHz), 6.75-7.21 (m, 4H); 13C NMR (CDCl3) δ 2.40, 28.13, 30.41, 32.33, 36.99, 38.86, 39.09, 69.74, 114.86, 116.00, 121.79, 129.28, 133.37, 136.42, 140.51, 155.66. MS m/e (rel intensity) 410 (42), 256 (19), 227 (75), 155 (18), 121 (100), 107 (32), 93 (28), 79 (14), 65 (16); Exact mass: calcd 410.0744, found: 410.0744. ##STR32##
Reaction SMILES: Cl[CH:2]([C:17](=O)[CH3:18])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:34][C:35]([NH2:37])=[S:36])[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1>C(O)C>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:34][C:35]2[S:36][C:2]([CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:16])([F:15])[CH:12]([F:14])[F:13])[CH:5]=3)=[C:17]([CH3:18])[N:37]=2)[CH:25]=[CH:26][C:27]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(=O)C(Cl)Cc1cccc(OC(F)(F)C(F)F)c1
Solvent: CCO
Product: COc1cc(Nc2nc(C)c(Cc3cccc(OC(F)(F)C(F)F)c3)s2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from crude 2-chloro-1-(3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl)-butan-3-one and 53 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (1 ml). The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 98 mg (96%) of the title compound as a brown solid. MS ISP (m/e): 507.3 (100) (M+H)+. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (s, 1H), 7.31 (t, 1H), 7.20 (s, 1H), 7.15-7.04 (m, 4H), 6.88 (d, 1H), 6.85 (s, 1H), 6.08-5.38 (tt, 1H), 3.99 (s, 2H), 3.81 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](O)[CH2:8][CH2:9]C.BrCCCCl.[CH:17]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.C1(C)C=CC=CC=1>[CH:17]([N:30]1[CH2:9][CH2:8][CH2:7]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCCCO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)N2CCC2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To A solution of 6.9 kg (50 moles) of potassium carbonate in 7.5 liters of water was added 18.5 liters of 1-butanol, 7.85 kg (50 moles) of 1-bromo-3-chloropropane and 5.18 kg (25 moles) of benzhydrylamine (97% purity with 10% toluene as a residual solvent). The reaction mixture was heated to 100° C. externally with steam and stirred slowly under a nitrogen gas atmosphere overnight. About 12 liters of water was added to the mixture to dissolve some inorganic salt precipitate. The layers were separated and organic layer was distilled under reduced pressure to remove about 18 liters of butanol and water. To the residue was added 1.5 liters of methanol and the resulting mixture was stirred slowly while cooling down to room temperature. The white solid was collected by filtration, rinsed twice with 700 ml portions of methanol and dried in a vacuum oven to give 4.2 kg (75%) of product, m.p. 107°-109° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54].Cl>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][O:41][S:53]([CH3:52])(=[O:55])=[O:54])=[CH:33][CH:32]=2)=[C:28]([CH:42]([CH3:44])[CH3:43])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCOS(C)(=O)=O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]methyl}-5-isopropyl-1H-pyrazole (2.21 g) in dichloromethane (35 mL) were added triethylamine (0.65 mL) and methanesulfonyl chloride (0.33 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-isopropyl-4-({4-[3-(methanesulfonyloxy)propoxy]phenyl)methyl}-1H-pyrazole. This material was dissolved in N,N-dimethylformamide (20 mL). To the solution was added sodium azide (0.46 g), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water three times, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate 1/1-1/3) to give the title compound (1.6 g).
Reaction SMILES: C(O[CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[N:29]([CH3:37])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:38])=[CH:13]1)C1C=CC=CC=1.[BrH:39]>C(O)(=O)C>[Br:39][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=2)[C:14]([N:22]2[C:26]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([F:36])[CH:34]=4)[N:29]([CH3:37])[CH:28]=3)=[N:25][NH:24][C:23]2=[O:38])=[CH:13]1
Reactant: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCOCc3ccccc3)c3ccc(F)cc23)c2cc(F)ccc21
Reactant: Br
Solvent: CC(=O)O
Product: Cn1cc(-c2n[nH]c(=O)n2-c2cn(CCCBr)c3ccc(F)cc23)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In a flask was added the compound obtained in Example 1, (1.0 g, 2.36 mmol) in acetic acid (30 mL). To this solution was added hydrobromic acid (33% in acetic acid, 8 mL), and the flask was sealed. The flask was heated with stirring in an oil bath (80° C.) for 12 hours. The reaction was monitored on LC-MS, which confirmed the completion of the reaction. The volatiles were removed in vaccuo, and the residue was partitioned between ethyl acetate and water (50+50 mL). The organic phase was washed twice with water and once with brine and evaporated to give a 1.1 g (97%) of the title compound as a crude product, pure enough to be used further without purification.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH3:8].[C:10]1([C:16](=[N:23][NH2:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1/[C:7](=[N:24]/[N:23]=[C:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)/[CH3:8]
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1sccc1Br
Solvent: CCO
Product: C/C(=N\N=C(c1ccccc1)c1ccccc1)c1sccc1Br
Temperature: 80 °C
Yield: 83.6 %

Procedure:
1-(3-Bromothiophen-2-yl)ethanone (8.0 g, 39.0 mmol) and (diphenylmethylene)hydrazine (8.42 g, 42.9 mmol) were dissolved in ethanol (75 mL). The reaction mixture was heated in an oil bath at 80° C. for 16 hours. Following reaction, the volatiles were evaporated, and the condensed mixture was purified via silica gel column chromatography, eluting with a gradient of 0-100% hexane and EtOAc. The pure fractions were combined and evaporated to give the title compound as a yellow solid (12.5 g, 84%). ESI-MS m/z [M+H]+ calc'd for C19H15BrN2S, 384. found, 384.
Reaction SMILES: [CH3:1][C:2]12[CH2:12][C:6]3([C:13]4[CH:18]=[C:17]([C:19]#[C:20][Si](C)(C)C)[CH:16]=[C:15]([C:25]#[C:26][Si](C)(C)C)[CH:14]=4)[CH2:7][C:8]([CH3:11])([CH2:10][C:4]([C:31]45[CH2:58][C:35]6([CH3:59])[CH2:36][C:37]([C:40]7[CH:45]=[C:44]([C:46]#[C:47][Si](C)(C)C)[CH:43]=[C:42]([C:52]#[C:53][Si](C)(C)C)[CH:41]=7)([CH2:39][C:33]([CH3:60])([CH2:34]6)[CH2:32]4)[CH2:38]5)([CH2:5]3)[CH2:3]1)[CH2:9]2.C(=O)([O-])[O-].[K+].[K+].O1CCCC1.Cl>CO>[CH3:60][C:33]12[CH2:39][C:37]3([C:40]4[CH:45]=[C:44]([C:46]#[CH:47])[CH:43]=[C:42]([C:52]#[CH:53])[CH:41]=4)[CH2:36][C:35]([CH3:59])([CH2:58][C:31]([C:4]45[CH2:10][C:8]6([CH3:11])[CH2:7][C:6]([C:13]7[CH:18]=[C:17]([C:19]#[CH:20])[CH:16]=[C:15]([C:25]#[CH:26])[CH:14]=7)([CH2:12][C:2]([CH3:1])([CH2:9]6)[CH2:3]4)[CH2:5]5)([CH2:38]3)[CH2:32]1)[CH2:34]2
Reactant: CC12CC3(C)CC(c4cc(C#C[Si](C)(C)C)cc(C#C[Si](C)(C)C)c4)(C1)CC(C14CC5(C)CC(C)(CC(c6cc(C#C[Si](C)(C)C)cc(C#C[Si](C)(C)C)c6)(C5)C1)C4)(C2)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(C#C)cc(C23CC4(C)CC(C)(C2)CC(C25CC6(C)CC(C)(CC(c7cc(C#C)cc(C#C)c7)(C6)C2)C5)(C4)C3)c1
Reaction time: 4 h

Procedure:
Next, 39.8 g (53.5 mmol) of the previously obtained 3,3′,5,5′-tetramethyl-7,7′-bis[3,5-bis(trimethylsilylethynyl)phenyl]-1,1′-biadamantane and 1.46 g (10.6 mmol) of potassium carbonate were stirred in a mixed solvent comprising 600 ml of tetrahydrofuran and 300 ml of methanol, for 4 hours under a nitrogen atmosphere at room temperature. This was added to 1000 ml of a 10% hydrochloric acid aqueous solution, and the precipitate was filtered and washed with 1000 ml of water and then with 1000 ml of acetone, after which it was dried to obtain 21.2 g of 3,3′,5,5′-tetramethyl-7,7′-bis(3,5-diethynylphenyl)-1,1′-biadamantane.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=6)[CH2:30][CH2:31]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: c1ccc(N2CCCNCC2)nc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCN(c2ccccn2)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 1-(pyridin-2-yl)-1,4-diazepane to give 227. MS: (ESI+)=473.1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([F:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=1>>[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:30]=[C:29]([F:31])[C:28]([NH2:32])=[C:27]([Cl:33])[CH:26]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Reactant: CNCCc1cc(F)c(N)c(Cl)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(F)c(N)c(Cl)c1)CC2

Procedure:
This compound was prepared analogous to Example 5(b) from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane and N-methyl-N-[2-(4-amino-3-chloro-5-fluoro-phenyl)-ethyl]-amine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:21]1[CH:26]=[C:25]([O:27][CH2:28][C@H:29]2[CH2:31][C@@H:30]2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[N:24]=[C:23]([CH3:39])[N:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[S:14][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:12][N:11]=1)[C:21]1[CH:26]=[C:25]([O:27][CH2:28][C@H:29]2[CH2:31][C@@H:30]2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[N:24]=[C:23]([CH3:39])[N:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc([C@H]2C[C@@H]2COc2cc(Cl)nc(C)n2)nc1
Reactant: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)s1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nnc(CN(C(=O)OC(C)(C)C)c2cc(OC[C@H]3C[C@@H]3c3ccc(C)cn3)nc(C)n2)s1
Temperature: 85 °C
Yield: 63 %

Procedure:
The mixture of ethyl 5-((tert-butoxycarbonylamino) methyl)-1,3,4-thiadiazole-2-carboxylate (9-5) (1.0 g, 3.48 mmol), 4-chloro-2-methyl-6-(((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methoxy)pyrimidine (9-6), Pd(OAc)2 (66 mg, 0.29 mmol), BINAP (199 mg, 0.319 mmol) and Cesium carbonate (1.133 g, 3.48 mmol) in toluene (10 mL) was heated to 85° C. under nitrogen for overnight. The solvent was removed under reduced pressure and the residue was purified by chromatography with gradient eluant (PE/EA=10/1; 5/1). The product was obtained as an orange syrup (1.0 g, 63%). 1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.35 (dd, J=7.9, 1.8 Hz, 1H), 7.19 (s, 1H), 7.05 (d, J=7.9 Hz, 1H), 5.59 (s, 2H), 4.50 (q, J=7.1 Hz, 2H), 4.35 (m, 2H), 2.53 (s, 3H), 2.27 (s, 3H), 2.13-2.03 (m, 1H), 1.89-1.87 (m, 1H), 1.48-1.43 (m, 12H), 1.32-1.24 (m, 1H), 1.05-1.02 (m, 1H); LRMS (ESI) calculated M+H for C26H32N6O5S: 541.6. Found: 541.2.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=1>>[Cl:10][C:11]1[N:12]=[C:13]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[CH:14]=[N:15][CH:16]=1
Reactant: NCc1ccc(F)cc1
Reactant: Clc1cncc(Cl)n1
Product: Fc1ccc(CNc2cncc(Cl)n2)cc1
Yield: 98.9 %

Procedure:
In a procedure analogous to example 1, reaction of 4-fluorobenzylamine (3.75 g, 30.0 mmol) and 2,6-dichloropyrazine (1.49 g, 10.0 mmol) furnished the product (2.35 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 90%). 1H NMR (200 MHz, CDCl3): δ 2.33 (s, 3H), 3.26-3.30 (m, 4H), 3.74-3.78 (m, 3H), 4.13 (s, 4H), 6.75-6.78 (m, 3H), 7.14-7.28 (m, 2H), 7.36 (s, 1H), 7.44-7.51 (dd, J=9.8 and 2.4 Hz, 1H), 7.67-7.74 (m, 1H).