Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[CH3:3][C:4]([CH3:15])([CH3:14])[C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].NCCCCN.C([Li])CCC.[I:27]I.[NH4+].[Cl-]>C(OCC)(=O)C.C(OCC)C>[I:27][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH:7][C:5](=[O:6])[C:4]([CH3:15])([CH3:14])[CH3:3]
Reactant: II
Reactant: CC(C)(C)C(=O)Nc1cccnc1
Agent: N#N
Agent: NCCCCN
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1cnccc1I
Temperature: -68 °C
Reaction time: 2.5 h
Yield: 23.3 %

Procedure:
Equip a 250-mL round bottom flask with a magnetic a stirrer, a thermocouple, a dry ice/acetone bath, a N2 atmosphere, and an addition funnel. Charge with 2,2-dimethyl-N-pyridin-3-yl-propionamide (3.0 g, 16.8 mmol), diethylether (67 mL), and tetramethylene diamine (4.68 g, 6.08 mL, 40.3 mmol). Cool the reaction to −78° C. Add slowly via glass syringe n-butyllithium (2.5 M solution in hexane, 16.2 mL, 40.3 mmol) over 10 min. Warm the reaction to −13° C. over 2 h. Cool the reaction to −78° C. Prepare an iodine solution (I2 8.5 g, 33.6 mmol in THF (20 mL)). Add the iodine solution to the reaction via the addition funnel and stir 2.5 h. at −68° C. Quench the reaction with the addition of a saturated NH4Cl solution (40 mL) and transfer into a separatory funnel. Add ethyl acetate (100 mL). Extract and discard the lower aqueous phase. Wash the organic layer with a saturated sodium thiosulfate solution (100 mL) and extract. Wash the organic phase with saturated aqueous sodium chloride and extract. Dry the organic phase over Na2SO4 and filter. Concentrate the product via rotary evaporation. Chromatograph on silica (80 g) eluting with gradient of 100% DCM to 70% ethyl acetate/30% DCM to afford 1.19 g (23%) of the title compound. MS (ES) m/z 306 [M+1]+.
Reaction SMILES: C(=O)(O)[O-].[Na+].[F:6][C:7]1[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:8]=1[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>CN(C)C=O>[CH3:24][N:25]([CH2:26][CH2:27][N:13]1[CH2:14][CH2:15][CH:10]([O:9][C:8]2[C:16]([F:23])=[C:17]([F:22])[C:18]([F:21])=[C:19]([F:20])[C:7]=2[F:6])[CH2:11][CH2:12]1)[CH3:29]
Reactant: Fc1c(F)c(F)c(OC2CCNCC2)c(F)c1F
Reactant: CN(C)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCC(Oc2c(F)c(F)c(F)c(F)c2F)CC1
Temperature: 85 °C
Reaction time: 5 h
Yield: 45.9 %

Procedure:
A stirred mixture of 5 g of sodium bicarbonate, 4.44 g of 4-(2,3,4,5,6-pentafluorophenoxy)piperidine, and 40 ml of dimethylformamide was treated, dropwise, with a solution of 2.15 g of 2-dimethylaminoethyl chloride in 20 ml of dimethylformamide. After stirring for five hours at 85° C., the reaction mixture was filtered, and the filtrate poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering, evaporation of the volatiles afforded an oil which was eluted with 20% methanol/dichloromethane on a silica gel column via flash chromatography. The desired fractions were evaporated to afford 2.58 g of 1-[2-(N,N-dimethylamino)ethyl]-4-(2,3,4,5,6-pentafluorophenoxy)piperidine as an oil. The oil was dissolved in isopropanol and the solution acidified to pH 1 with etheral hydrogen chloride to precipitate 2.05 g (29.3%) of the corresponding dihydrochloride salt, m.p. 276° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]([C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:22][C:23]([N:25]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]2)=[O:24])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([C:38](=[O:47])/[CH:39]=[CH:40]/[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:22][C:23]([N:25]3[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]3)=[O:24])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(O)cc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)CN(C(=O)/C=C/c2ccccc2)c2ccc(OCc3ccc(OC(F)(F)F)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4-Trifluoromethoxybenzyl bromide (17 μL) was added to a mixture of [(S)-1-(2-{(4-hydroxyphenyl)-[(E)-(3-phenylacryloyl)]amino}acetyl)pyrrolidin-3-yl]-carbamic acid, tert-butyl ester 14 (50 mg, 0.11 mmol), cesium carbonate (52 mg, 0.16 mmol) and TBAI (40 mg, 0.11 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed with 10% hydrochloric acid (×2) and brine, dried (Na2SO4) and evaporated to dryness. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petrol (2:1) to afford the title compound as a colourless foam (52 mg, 75%). 1HNMR (300 MHz) (CDCl3) 1.41 (9H, s), 1.7-2.2 (2H, m), 3.35-3.8 (4H, m), 4.15-4.35 (2H, m), 4.5 (1H, m), 4.7-4.9 (1H, m), 5.00 (2H, s), 6.37 (1H, d, J=16 Hz), 6.95 (2H, d), 7.18-7.30 (7H, m), 7.32 (2H, d), 7.45 (2H, d) and 7.64 (1H, d, J=16 Hz).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([NH:14][C:15]2[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[CH3:26])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:27]([Si:31]([CH3:40])([CH3:39])[O:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:31]([O:32][CH:33]1[CH2:34][CH2:35][N:36]([C:2]2[CH:11]=[C:10]([C:12]([NH:14][C:15]3[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=3[CH3:26])=[O:13])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:37][CH2:38]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:40])[CH3:39]
Reactant: COC(=O)c1cc(C)c(NC(=O)c2cc(Cl)nc3ccccc23)c(C)c1
Reactant: CC(C)(C)[Si](C)(C)OC1CCNCC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(NC(=O)c2cc(N3CCC(O[Si](C)(C)C(C)(C)C)CC3)nc3ccccc23)c(C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of methyl 4-(2-chloroquinoline-4-carboxamido)-3,5-dimethylbenzoate, (0.50 g, 0.00135 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.32 g, 0.0015 mol, see preparation 3) and Cs2CO3 (1.77 g, 0.0054 mol) in 1,4-dioxane (5 ml) is added Pd2(dba)3 (0.124 g, 0.000135 mol) followed by S-Phos (0.060 g, 0.000135 mol). The reaction mixture is purged with nitrogen for 5 minutes and then stirred at 80° C. After 4 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (0.21 g, 28%). Mass spectrum (m/z): 548.2 (M+1).
Reaction SMILES: C[N:2](C)/C=C/C(C1SC(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)=NC=1C)=O.C[N:32](C)/[C:33](/[CH3:60])=[CH:34]/[C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[C:43]2=[O:58])=[N:39][C:38]=1[CH3:59])=O.O.NN>>[CH3:59][C:38]1[N:39]=[C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)[C:43]2=[O:58])[S:41][C:37]=1[C:35]1[CH:34]=[C:33]([CH3:60])[NH:32][N:2]=1
Reactant: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Agent: NN
Solvent: O
Product: Cc1cc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n[nH]1
Yield: 67 %

Procedure:
Following the procedure as described in Example 38, making variations as required to replace (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one with (E)-1-(5-(3-(dimethylamino)but-2-enoyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one to react with hydrazine monohydrate, the title compound was obtained as a colorless solid in 67% yield: mp 238-239° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 6.08 (s 1H), 4.52 (s, 2H), 4.04-3.99 (m, 2H), 3.42-3.36 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.8, 155.8, 143.1, 139.9, 130.3, 129.9, 128.3, 125.8, 125.7, 122.1, 103.6, 47.5, 41.9, 41.8, 16.0, 10.8; MS (ES+) m/z 422.1 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[CH3:13])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: CNCc1c(C)oc2ccccc12
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1oc2ccccc2c1CN(C)C(=O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Yield: 68 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(2-methyl-benzofuran-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.24 g, 68%) was prepared as a white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.86 (br s, 1H), 10.47 (br s, 1H), 8.54 (br s, 1H), 8.38-8.29 (m, 1H), 7.78-7.46 (m, 3H), 7.32-7.15 (m, 3H), 4.97-4.74 (m, 2H), 4.02-3.91 (m, 5H), 3.87-3.79 (m, 4H), 3.63 (br s, 2H), 3.45-3.29 (m, 4H), 3.27-3.15 (m, 4H), 3.07-2.82 (m, 3H), 1.93 (br s, 2H); MS (ESI) m/e 518 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][Si](C)(C)C)=[C:4]([F:14])[CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([F:14])[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1ccc(Cl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: C#Cc1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.2 %

Procedure:
To a solution of ((4-chloro-2-fluorophenyl)ethynyl)trimethylsilane (1.0 g, 4.42 mmol) in DCM (20 mL) was added TBAF (catalytic) and reaction mixture was stirred for 1-2 h at RT. The reaction mass was quenched in water, extracted with DCM and concentrated to afford 0.900 g of the crude product which was further purified by column chromatography eluting with pet. ether to afford to afford 0.500 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 4.60 (s, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.56-7.61 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([CH2:15][NH2:16])[OH:14]>O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:10]([O-:12])=[O:11])=[C:2]([NH:16][CH2:15][CH2:13][OH:14])[CH:7]=1
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1
Reactant: NCCO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NCCO)c1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
A round bottom flask was charged with 2-bromo-4-methoxy-1-nitrobenzene (2.0 g, 8.6 mmol) and ethanolamine (8.1 mL, 135 mmol). The resulting reaction mixture was stirred at 50° C. for 4 h and at rt for 48 h, then water (32.0 mL) was added and the resulting precipitate was filtered off and rinsed with water to yield 2-((5-methoxy-2-nitrophenyl)amino)ethanol as a yellow solid LC-MS conditions B: tR=0.56 min, [M+H]+=213.13.
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH:30](Cl)[CH3:31])=[O:28].C(N(CC)CC)C.ClC(OCC)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.ClCCl.C1COCC1>[CH2:30]([O:29][C:27]([N:2]1[CH2:7][CH2:6][C:5]2([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1)=[O:28])[CH3:31]
Reactant: CN1CCC2(CCOc3ccccc32)CC1
Reactant: CC(Cl)OC(=O)Cl
Agent: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC2(CCOc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A stirred solution of 2,3-dihydro-1'-methylspiro[4H-benzopyran-4,4'-piperidine] (D101, 1.0 g, 0.0046 mole) and diisopropylethylamine (1.2 ml, 0.0070 mole) in dichloroethane (20 ml) was treated with 1-chloroethyl chloroformate (0.64 ml, 0.0060 mole) and kept at room temp. for 1 h followed by 20 mins at reflux. The solution was then concentrated in vacuo and the residue treated with methanol (20 ml) and heated under reflux for 2 h. The reaction mixture was concentrated in vacuo to leave a beige solid, which was dissolved in dichloromethane (50 ml) and THF (10 ml) and treated with triethylamine (0.84 ml, 0.0060 mole) followed by ethyl chloroformate (0.44 ml, 0.0046 mole). The solution was stirred at room temperature for 2 h, then treated with 10% Na2CO3 solution (20 ml) and extracted with dichloromethane (2×40 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 1:1 ether/60-80 petrol to afford the title compound as a yellow oil (1.3 g, 100%).
Reaction SMILES: C([N:4]1[CH:8]=[CH:7][N:6]=[C:5]1[C:9]1[S:13][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)=[N:11][C:10]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])C=C.C1([SiH3])C=CC=CC=1>ClCCl.C(O)(=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>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[S:13][C:9]=1[C:5]1[NH:4][CH:8]=[CH:7][N:6]=1
Reactant: C=CCn1ccnc1-c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccc(Cl)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [SiH3]c1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3ncc[nH]3)s2)ccn1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of N-{4-[5-(1-Allyl-1H-imidazol-2-yl)-4-(2,4-dichlorophenyl)-1,3-thiazol-2-yl]pyridin-2-yl}acetamide (0.0650 g, 0.138 mmol) in dichloromethane (1.0 mL) and acetic acid (0.34 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.00798 g, 0.00691 mmol) followed by phenylsilane (0.0870 mL, 0.706 mmol). The solution was stirred at 40° C. for 90 minutes. The solution was cooled to room temperature then concentrated in vacuo and diluted with ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted 3 more times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (0.0380 g, 64%). LCMS: (FA) ES+, 431, 433. 1H NMR (400 MHz, d4-Methanol) δ: 8.75-8.70 (m, 1H), 8.44-8.39 (m, 1H), 7.70-7.44 (m, 4H), 7.13-7.07 (m, 2H), 2.20 (s, 3H).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][C:7]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:8])[C:3]([OH:5])=[O:4].[CH2:15]([S:19]([OH:21])=[O:20])[CH:16]([CH3:18])[CH3:17].C(#N)C>C1(C)C=CC=CC=1>[CH3:17][CH:16]([CH3:18])[CH2:15][S:19]([CH2:1][CH:2]([CH2:6][C:7]([N:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)=[O:8])[C:3]([OH:5])=[O:4])(=[O:21])=[O:20]
Reactant: CC(C)CS(=O)O
Reactant: C=C(CC(=O)N1CCOCC1)C(=O)O
Solvent: CC#N
Solvent: Cc1ccccc1
Product: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 28 %

Procedure:
A mixture of 2-Methylene-4-morpholin-4-yl-4-oxo-butyric acid (3.98 g, 20 mmol) and isobutyl-sulphinic acid (2.44 g, 20 mmol) were suspended in anhydrous toluene (80 mL) and anhydrous acetonitrile (20 mL). This mixture was warmed to 85° C. and stirred vigorously for 4.5 h. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was purified by flash chromatography using a 90 g silica gel column eluting with 10% methanol/CH2Cl2. Recovered 3.7 g of product as an oil. Triturated residue with isopropanol (5 mL)/ether (100 mL). Product began to precipitate out. Cooled this to 5° C. for 17 hrs(overnight). Product was collected by filtration, washed with ether and dried under vacuum to give 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid as a white solid (1.8 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:3]=1.[N+:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][C:28]=1[NH2:29])([O-:22])=[O:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(CC)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]([F:19])=[C:12]([C:4]2[CH:3]=[C:2]([NH:29][C:28]3[CH:27]=[CH:26][N:25]=[CH:24][C:23]=3[N+:20]([O-:22])=[O:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=1
Reactant: Nc1ccncc1[N+](=O)[O-]
Reactant: Fc1ccc(Cl)cc1-c1cc(Br)c2ccccc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: O=[N+]([O-])c1cnccc1Nc1cc(-c2cc(Cl)ccc2F)nc2ccccc12

Procedure:
10 g 4-Bromo-2-(5-chloro-2-fluoro-phenyl)-quinoline (cf. Example 5; M 336.59), and 4.13 g of 3-nitro-4-amino pyridine in 500 ml tert. amylalcohol were treated under argon with 272 mg Pd2(dba)3 (ABCR) and 0.69 g Xanthphos (ABCR) under basic conditions adjusted with 12.6 g K3PO4 at 117° C. external (100° C. internal temperature) for 6.5 hrs. Work-up with ethyl acetate extract washed with aqueous 5% KHSO4 solution (pH 2) and aqueous 5 NaHCO3 solution yielded after drying with Na2SO4, filtration and washings with methanol 6.6 g yellow powder of correct mass M+H+ 395 and Rt˜2.67 min and Rf˜0.44 in TLC on silica in petrolether/EE 2:1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:24]=[CH:23][N:22]=[C:21]([C:25]([N:36]5[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]5)=[O:27])[CH:20]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: N#CC1CNC1
Reactant: CC1Cc2ccc(-c3ccnc(C(=O)O)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccnc(C(=O)N4CC(C#N)C4)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 61A starting from 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 61A, Step 2) and azetidine-3-carbonitrile hydrochloride (Astatech, Cat. No. 52028). (M+H)+: m/z=524.3.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[C:13]2=[O:34])=[N:8][N:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH2:35]([O:37][C:38]1[C:47]([O:48][CH3:49])=[CH:46][C:45]2[C:44]([C:50]3[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=3)=[N:43][C@@H:42]3[CH2:59][CH2:60][S:61][CH2:62][C@@H:41]3[C:40]=2[CH:39]=1)[CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:17]3[CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[S:20][C:16]=3[C:15](=[O:27])[N:14]([CH:28]3[CH2:29][CH2:30][N:31]([C:54]([C:53]4[CH:57]=[CH:58][C:50]([C:44]5[C:45]6[CH:46]=[C:47]([O:48][CH3:49])[C:38]([O:37][CH2:35][CH3:36])=[CH:39][C:40]=6[C@H:41]6[CH2:62][S:61][CH2:60][CH2:59][C@H:42]6[N:43]=5)=[CH:51][CH:52]=4)=[O:55])[CH2:32][CH2:33]3)[C:13]2=[O:34])=[N:8][N:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnc(C(C)(C)C)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(5-tert-butyl-1,3,4-oxadiazol-2-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (1.63 g; compound B98) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (1.39 g; compound C10) and HBTU (1.48 g) in DCM (40 ml) in the presence of DIPEA (2.38 ml) according to the procedure described in example 55 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluent: EtOAc/cyclohexane, 90/10 (v/v)] as a solid
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:30](=[O:31])[N:7]2[CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:32])[C:5]1=[O:33])=[CH:15][C:14]([O:19][CH:20]([F:22])[F:21])=[CH:13][CH:12]=4.[CH3:34][NH:35][CH3:36]>>[F:22][CH:20]([F:21])[O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[N:7]3[C:30](=[O:31])[N:4]([CH2:3][CH2:2][N:35]([CH3:36])[CH3:34])[C:5](=[O:33])[C:6]3([CH3:32])[CH2:18][C:17]2=1
Reactant: CC12Cc3c([nH]c4ccc(OC(F)F)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Reactant: CNC
Product: CN(C)CCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(OC(F)F)cc4c3CC2(C)C1=O

Procedure:
The title compound is prepared similarly as described for example 29 using (3aSR,10RS)-2-(2-Bromoethyl)-6-(1,1-difluoro-methoxy)-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 36) and dimethyl amine instead of azetidine as starting materials. MS: m/z (MH+)=485.2