Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([Cl:18])=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([C:27]#[CH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>O1CCCC1.[Cu](I)I.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.O>[Cl:18][C:11]1[CH:10]=[CH:9][C:8]([C:6](=[O:7])[C:5]2[CH:19]=[CH:20][C:2]([C:28]#[C:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:3][CH:4]=2)=[CH:13][C:12]=1[S:14]([NH2:17])(=[O:16])=[O:15]
Reactant: NS(=O)(=O)c1cc(C(=O)c2ccc(Br)cc2)ccc1Cl
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1cc(C(=O)c2ccc(C#Cc3ccccc3)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a degassed solution of 5-(4-bromo-benzoyl)-2-chloro-benzenesulfonamide (500 mg, 1.33 mmol), phenylacetylene (204 mg, 2.00 mmol), copper iodide (15 mg), triphenylphosphine (9 mg, 0.033 mmol) and triethylamine (0.278 mL, 2 mmol) in tetrahydrofuran (4 mL) is added dichlorobis(triphenylphosphine)-palladium (47 mg, 0.067 mmol). The reaction mixture is allowed to stir at room temperature for 18 hours then poured into water (25 mL) and extracted twice with ethyl acetate. The organic fractions are combined, washed twice with a saturated sodium chloride solution, dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting residue is purified via silica gel chromatography (20-50% ethyl acetate in hexanes) to yield the title compound as a white solid. MS (m/z): 394 (M−1).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:38]2[NH:37][CH2:36][CH2:35][O:34][C:33]=2[CH:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][CH2:36][NH:37][C:38]=2[C:29]=1[Cl:28])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Reactant: CC1(C)OB(c2ccc3c(c2Cl)NCCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3ccc4c(c3Cl)NCCO4)n2n1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (400 mg, 0.817 mmol), 5-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (prepared according to the procedure described in WO 2009/062285; 290 mg, 0.981 mmol) and 2N Na2CO3 (0.817 mL, 1.635 mmol) in DMF (8 mL) was degassed for 15 min. Tetrakis(triphenylphosphine)palladium(0) (66.1 mg, 0.057 mmol) was added and the degassing was continued for another 5 min. The mixture was then heated at 90° C. for 16 h. At this point LCMS indicated completion of reaction and presence of desired product. After cooling to room temperature, water was added (25 mL) and the mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude was purified by biotage (5-70% EtOAc/hexane) to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(5-chloro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (315 mg, 0.593 mmol, 72.6% yield) as a mixture of two atrope isomers which are not separable (approx 10-15% of minor atrope isomer present by LCMS and NMR). Mixture was used as is in the next step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].C(OC(N1CCCC(N(C(=O)C)CC2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)C2C=C([Br:75])C(C)=CC1=2)=O)(C)C>>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:17]=[C:18]([C:26]([F:27])([F:29])[F:28])[CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=2)[C:9]2[CH:33]=[C:34]([Br:75])[C:35]([F:37])=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(C)c(Br)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)ccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(F)c(Br)cc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 56 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-fluoro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate following the procedure of Example 56 for the synthesis of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-methyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. ESI MS 613 (M+H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:25][CH2:24]1)(C(C)(C)C)(C)C.O1CCCC1.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(O)(=O)C>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[CH:29][C:30]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:31])[CH2:25][CH2:24]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(=CC(=O)OCc3ccccc3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(C=C1CCC(c2ccc(O)cc2O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
To a round bottomed flask equipped with magnetic stirrer was added benzyl [4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]acetate (232 mg), tetrahydrofuran (5 ml), tetrabutylammonium fluoride hydrate (429 mg) and glacial acetic acid (94 μl). After stirring at room temperature for 0.5 hr, the solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (20 ml). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with water (50 ml), brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether, 1:3 v/v) furnished the title compound (100 mg, 72%) as a cream solid. δH (CD3OD): 1.59-1.67 (2H, m), 1.98-2.13 (4H, m), 2.37-2.48 (2H, m), 3.14 (1H, ft), 5.16 (2H, s), 5.75 (1H, s), 6.26 (1H, dd), 6.30 (1H, d), 6.89 (1H, d), 7.30-7.44 (5H, m); m/z (ES+) 337 (M−H)−.
Reaction SMILES: [Sn].[C:2]([C:6]1[CH2:11][C:10](C(C)(C)C)(C)[CH:9]=[CH:8][C:7]=1O)(C)(C)[CH3:3]>CO>[CH2:3]=[CH:2][CH:6]=[CH2:7].[CH2:3]=[CH:2][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)C1=C(O)C=CC(C)(C(C)(C)C)C1
Agent: [Sn]
Solvent: CO
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
A 5-liter stainless steel autoclave is purged with nitrogen and then is charged with a mixture of 70 g of styrene, 2053 g of cyclohexane and 210 g of butadiene. Afterwards, the autoclave is heated in a water bath under stirring to reach a temperature of 50° C. and at that temperature, butyllithium is added to remove the impurities reactive to the initiator, followed by 8.4 mmol of the tin-containing organolithium initiator from Example 63. The reaction mixture is allowed to react for 2 hours and then 10 ml of methanol and 1.6 g of 2,4-di-tert.-butyl-4-methylphenol are added. The content of the autoclave is discharged, and coagulated with steam to remove the solvent and the regulator, then dried to a constant weight. GPC measurements show that the polymer obtained has a weight average molecular weight of 120,000, a number average molecular weight of 110,000, and a molecular weight distribution of 1.09.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:3]1=[O:34].[Li+].CC([N-]C(C)C)C.[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1>C1COCC1.CC(=O)OCC.O>[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]([OH:49])[C:11]2[C:6]3[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[C:3](=[O:34])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=2)=[CH:46][CH:45]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(C(F)(F)F)c3)cnc21
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (340 mg, 0.708 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 1.42 mL, 2.83 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (199.7 mg, 1.42 mmol) in THF (2 mL) was added dropwise. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (172 mg, 39.1% yield) as an oil. LCMS: [MH+-THP] 537 and TR=1.611 min.
Reaction SMILES: C([Li:5])CCC.[C:6]1([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20]1(C)C=C[CH:23]=[CH:22][CH:21]=1>>[C:6]1([C:12]([Li:5])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:20][CH2:21][CH2:22][CH3:23])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [Li]CCCC
Reactant: C=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Product: [Li]C(CCCCC)(c1ccccc1)c1ccccc1

Procedure:
1,1-Diphenylhexyllithium was prepared by reacting n-butyllithium with 1,1-diphenylethylene in toluene at 40° C. for 72 h.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[N:32](COCC[Si](C)(C)C)[C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[C:41]3[CH:42]=[N:43][N:44](COCC[Si](C)(C)C)[CH:45]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3N(COCC[Si](C)(C)C)C4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:22](=[O:23])[C:17]=4[C:16]=3[C:41]3[CH:42]=[N:43][NH:44][CH:45]=3)[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2c(-c3ccc(OC(F)F)c(OC4CC4)c3)n(COCC[Si](C)(C)C)c3cnn(COCC[Si](C)(C)C)c(=O)c23)cn1
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: C[Si](C)(C)CCOCn1ncc2[nH]c(-c3ccc(OC(F)F)c(OC4CC4)c3)c(-c3cn[nH]c3)c2c1=O
Yield: 79.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(b) except for using 190 mg (0.241 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-1,5-bis(2-trimethylsilylethoxymethyl)-3-[1-(2-trimethylsilylethoxymethyl)-1H-pyrazol-4-yl]-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 18-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one, whereby 101 mg of the title compound was obtained as a white solid. (Yield: 79%)
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:23])[N:12]([CH2:14][CH2:15][O:16]C3CCCCO3)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[C:24]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:23])[N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: O
Solvent: CO
Product: O=c1ccc(C(c2ccccc2)c2ccccc2)cn1CCO
Reaction time: 48 h
Yield: 55.5 %

Procedure:
To a stirring solution of 5-(diphenylmethyl)-1-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2(1H)-pyridinone (46 mg) in MeOH (1.38 mL) was added pyridium p-toluenesulfonate (9 mg) at ambient temperature. After 48 hours, water was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform:EtOAc=1:2) to give 5-(diphenylmethyl)-1-(2-hydroxyethyl)-2(1H)-pyridinone (20 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1.[SH:20][C:21]1[N:25]([CH3:26])[CH:24]=[N:23][N:22]=1>>[CH3:26][N:25]1[CH:24]=[N:23][N:22]=[C:21]1[S:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][N:15]=1
Reactant: Clc1ncnc2ccc(I)cc12
Reactant: Nc1ccncn1
Reactant: Cn1cnnc1S
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3ccncn3)c2c1

Procedure:
The compound of Example 18 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 4-aminopyrimidine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:20]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:19])C)[CH3:2].[CH:23]([N:36]1[CH2:39][C:38](OS(C)(=O)=O)([CH3:40])[CH2:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:18][C:38]3([CH3:40])[CH2:39][N:36]([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37]3)[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:19])[CH3:20])[CH3:2]
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C(C)(CC)N1C(=O)COc2cc(F)c(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CN(C(c4ccccc4)c4ccccc4)C3)cc21
Temperature: 90 °C
Reaction time: 3 h
Yield: 76.5 %

Procedure:
A mixture of ethyl 2-(7-fluoro-6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.200 g, 0.706 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (Preparation #3, Step B, 0.257 g, 0.777 mmol) and Cs2CO3 (0.460 g, 1.412 mmol) in DMF (8 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give 2-[7-fluoro-6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester as a white solid (0.280 g, 76%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.31 (m, 2H), 7.29 (m, 2H), 7.27 (m, 2H), 6.87 (d, J=10.4 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 5.45 (q, J=7.2 Hz, 1H), 4.55 (d, J=15.2 Hz, 2H), 4.41 (s, 1H), 3.98 (q, J=7.2 Hz, 2H), 3.34 (d, J=7.6 Hz, 2H), 3.19 (d, J=7.6 Hz, 2H), 1.59 (s, 3H), 1.56 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=3[CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=3)(=[O:35])=[O:34])=[CH:7][CH:6]=2)[C:14](=[O:15])[CH2:13]1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: COc1cccc(S(=O)(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3c4CCCC3)cc2)c1
Yield: 48.3 %

Procedure:
5-(4-Aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (65 mg, 0.202 mmol) obtained in Example 55, and 3-methoxybenzenesulfonyl chloride (63 mg, 0.305 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (48 mg, yield 48%) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@H:9]([NH2:18])[CH2:8][N:7]4[CH3:19])=[CH:3]1.[C:20]([N:27]1[CH:31]=[CH:30]N=[CH:28]1)(N1C=CN=C1)=[S:21].[CH2:32](NCC)C>>[CH3:1][N:2]1[C:16]2[C:17]3[C:4]([CH2:5][C@@H:6]4[C:11]([C:12]=3[CH:13]=[CH:14][CH:15]=2)=[CH:10][C@H:9]([NH:18][C:20](=[S:21])[N:27]([CH2:31][CH3:30])[CH2:28][CH3:32])[CH2:8][N:7]4[CH3:19])=[CH:3]1
Reactant: CN1C[C@@H](N)C=C2c3cccc4c3c(cn4C)C[C@H]21
Reactant: CCNCC
Reactant: S=C(n1ccnc1)n1ccnc1
Product: CCN(CC)C(=S)N[C@H]1C=C2c3cccc4c3c(cn4C)C[C@H]2N(C)C1
Yield: 67 %

Procedure:
One millimole of 9,10-didehydro-1,6-dimethylergoline-8α-amine is reacted with 1,1'-thiocarbonyldiimidazole and diethylamine, as described in Example 11, to 3-(9,10-didehydro-1,6-dimethyl-8α-ergolinyl)-1,1-diethylthioruea. After chromatography, 3-(9,10-didehydro-1,6-dimethyl-8α-ergolinyl)-1,1-diethylthiourea is obtained in a 67% yield. By dissolution with the equivalent quantity of L-tartaric acid in methylene chloride and methanol, 3-(9,10-didehydro-1,6-dimethyl-8α-ergolinyl)-1,1-diethylthiourea tartrate is obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:40])[NH:11][CH:12]([C:19]1[CH:24]=[C:23](Br)[CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:40])[NH:11][CH:12]([C:19]1[CH:24]=[C:23]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]3[O:39][CH2:38][CH2:37][O:36]3)[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2
Reactant: O=C(NC(c1ccccc1)c1cc(Br)cc(OCCCCCCCCC2OCCO2)c1)O[C@H]1CN2CCC1CC2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NC(c1ccccc1)c1cc(OCCCCCCCCC2OCCO2)cc(-c2ccccc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 120 °C
Yield: 69.2 %

Procedure:
To a stirred solution of (R)-quinuclidin-3-yl((3-((8-(1,3-dioxolan-2-yl)octyl)oxy)-5-bromophenyl)(phenyl)methyl)carbamate (0.2 g, 0.33 mmol) (prepared in Example 28 Step 8) in toluene (4 mL) and water (1 mL), was added phenyl boronic acid (0.04 g, 0.33 mmol), sodium carbonate (0.07 g, 0.66 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.04 g, 0.03 mmol). The reaction mixture was heated in the microwave at 120° C. for 30 minutes. The solvent was removed under reduced pressure, diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were dried (sodium sulphate), filtered and solvent removed under reduced pressure. The crude material was purified by silica gel chromatography eluting with 0-10% methanol in ethyl acetate to afford the title compound as a colourless oil (0.14 g, 71%).
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)[C:3]([Cl:5])=[O:4].BrC(C1C=CC(Cl)=CC=1)C([Cl:17])=O.BrC1C=C(CC(O)=O)C=CC=1.S(Cl)(Cl)=O.BrBr>>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:17])[CH:7]=1)[C:3]([Cl:5])=[O:4]
Reactant: O=C(Cl)C(Br)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(Br)c1cccc(Br)c1
Agent: BrBr
Agent: O=C(O)Cc1cccc(Br)c1
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C(Br)c1cccc(Cl)c1

Procedure:
(RS)-2-Bromo-2-(3-bromophenyl)acetyl chloride may be prepared by the method described in Example 9 for the preparation of (RS)-2-bromo-2-(4-chlorophenyl)acetyl chloride, but using 5 g of 2-(3-bromophenyl)acetic acid, 2.8 cm3 of thionyl chloride and 1.5 cm3 of bromine as starting materials. 7 g of (RS)-2-bromo-2-(3-chlorophenyl)acetyl chloride are then obtained, which is used as such for the following step.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[CH3:9][CH:10]([SH:12])[CH3:11].C(O)CO.C(=O)([O-])[O-].[K+].[K+]>CC(O)C.[Cu]I>[CH:10]([S:12][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1)([CH3:11])[CH3:9]
Reactant: CC(C)S
Reactant: Oc1ccc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)Sc1ccc(O)nc1
Reaction time: 0.75 h

Procedure:
5-iodopyridin-2-ol (1 g, 4.525 mmol), propane-2-thiol (689.3 mg, 840.6 μL, 9.050 mmol), ethylene glycol (842.9 mg, 757.3 μL, 13.58 mmol), CuI (172.4 mg, 0.9050 mmol) and potassium carbonate (1.877 g, 13.58 mmol) in IPA (7 mL) were heated under microwave conditions at 120° C. for 2 hours. The mixture was filtered through celite washing with DCM and the filtrate concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 0 to 100% EtOAc/Petroleum Ether, loaded in DCM). The fractions were combined and concentrated in vacuo and the residue redissolved in EtOAc (10 mL) and stirred with 0.5 g of 3-Mercaptopropyl ethyl sulfide Silica for 45 minutes. The silica was removed by filtration and the solvent removed in vacuo to give the sub-title compound as a beige oil which was used without further purification.