Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[CH2:11]([Li])CCC.[CH2:16]([CH2:23][NH:24][C:25](=[O:37])[CH2:26][CH2:27][CH2:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19]C=1>CCCCCC.O1CCCC1>[CH2:23]([N:24]([CH3:11])[C:25](=[O:37])[CH2:26][CH2:27][CH2:28][C:29]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:5][C:3]([OH:4])=[CH:2][C:1](=[O:6])[O:36]1)[C:16]1[CH:17]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)CC(C)=O
Reactant: [Li]CCCC
Reactant: O=C(CCCC(=O)c1ccccc1)NCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(Cc1ccccc1)C(=O)CCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 5.6 mmol of methyl acetoacetate, 6.1 mmol of NaH 60% dispersion in oil, 5.9 mmol of 1.6M n-butyl lithium in hexane, 5.6 mmol of 5-oxo-5-phenylpentanoic acid benzylmethyl amide and 25 mL of tetrahydrofuran. The product was flash chromatographed using CH2 Cl2 /MeOH (98/2) to give a solid (m.p. 47°-51° C.). 1H NMR (DMSO-d6) δ1.1-1.3 (m, 1H), 1.4-1.6 (m, 1H), 1.8-2.0 (m, 2H), 2.2-2.4 (m, 2H), 2.75/2.81 (s/s 3H), 2.85-3.1 (m, 2H), 4.4/4.5 (s/s, 2H), 4.85/4.9 (s/s 1H), 7.1-7.4 (m, 10H), 11.36/11.38 (s/s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CC#N>[Cl:41][C:37]1[CH:36]=[C:35]([N:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH2:26][N:8]3[C:9](=[O:11])[C:10]4[C:2]([CH3:1])=[C:3]([C:12]([N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)=[O:13])[S:4][C:5]=4[N:6]=[CH:7]3)[CH2:34][CH2:33]2)[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(CCl)N1CCN(c2cccc(Cl)c2)CC1
Reactant: Cc1c(C(=O)N2CCCC2)sc2nc[nH]c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(C(=O)N2CCCC2)sc2ncn(CC(=O)N3CCN(c4cccc(Cl)c4)CC3)c(=O)c12
Yield: 21.7 %

Procedure:
To a suspension of 5-methyl-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (0.06 g, 0.23 mmol) in CH3CN (5 mL) was added K2CO3 (0.032 g, 0.23 mm (38 mg, 0.23 mmol), and 2-chloro-1-(4-(3-chlorophenyl)piperazin-1-yl)ethanone, (0.062 g, 0.23 mmol). The reaction mixture was refluxed overnight and then quenched with H2O (20 mL). The resultant precipitate was filtered and dried to provide a crude solid which was purified by flash chromatography (Et2O:DCM, 1:1) providing 0.025 g of pure 3-(2-(4-(3-chlorophenyl)piperazin-1-yl)-2-oxoethyl)-5-methyl-6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4(3H)-one, (yield: 22%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]4[C:23](=[CH:24][C:25]#N)[C:22]5[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=5[CH2:20][O:19][C:18]=4[CH:31]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:32])[CH:3]=1.[OH-:33].[Na+].C(O)CO.[OH2:39]>>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]4[C:23](=[CH:24][C:25]([OH:39])=[O:33])[C:22]5[CH:27]=[CH:28][CH:29]=[CH:30][C:21]=5[CH2:20][O:19][C:18]=4[CH:31]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:5]2=[C:4]([CH3:32])[CH:3]=1
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)OCc1ccccc1C2=CC#N
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: OCCO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)OCc1ccccc1C2=CC(=O)O
Yield: 49 %

Procedure:
A mixture of 88 mg of Compound 2, 2 ml of a 1N aqueous solution of sodium hydroxide and 5 ml of ethyleneglycol was heated under reflux for 48 hours. After cooling, the mixture was diluted with water and washed with ether, and the aqueous layer was adjusted to pH 4 with 4N aqueous hydrochloric acid. The resulting precipitate was separated from the mixture by filtration and washed with water to give 44.7 mg (49%) of the product as a white solid.
Reaction SMILES: C(O)(=O)C.[C:5]([C:9]1[CH:10]=[C:11]([CH3:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6].[Br:17]Br>O>[C:5]([C:9]1[CH:10]=[C:11]([CH3:16])[C:12]([Br:17])=[C:13]([CH3:15])[CH:14]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: Cc1cc(C)cc(C(C)(C)C)c1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C(C)(C)C)cc(C)c1Br
Yield: 94.7 %

Procedure:
Under an inert atmosphere, 225 g of acetic acid was put into a 500 ml three-necked flask, and 24.3 g of 5-t-butyl-m-xylene was added. Then, after adding 31.2 g of bromine, it was reacted at 15-20° C. for 3 hours. The reaction liquid was added to 500 ml of water, and the deposited precipitate was filtrated. It was washed with 250 ml of water twice and 34.2 g of white solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[S:22])=[C:16]([CH2:19][CH3:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([OH:23])=[S:22])=[C:16]([CH2:19][CH3:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: CCC1=C(C(=S)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCC1=C(C(O)=S)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cccc(N)n3)[C@H]2SC1
Yield: 55.9 %

Procedure:
The solution of benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylate (syn isomer, 2.3 g) in trifluoroacetic acid (10 ml) and anisole (2 ml) was stirred for 2 hours at ambient temperature. The resultant solution was poured into diisopropyl ether (300 ml) and the precipitates were collected by filtration. The precipitates were dissolved in an aqueous solution of sodium bicarbonate (pH 7.5). The aqueous solution was washed with ethyl acetate and was adjusted to pH 2.3 with 10% hydrochloric acid. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 7-[2-(6-aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-ethylthio-3-cephem-4-carboxylic acid (syn isomer, 0.87 g), mp. 164° to 167° C. (dec.).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30](=[O:32])[CH3:31])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[C:33]1([Mg]Br)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)([OH:32])[CH3:31])[CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3]
Reactant: Br[Mg]c1ccccc1
Reactant: CC(=O)c1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1cccc(-c2cccc(-c3cc(C(C)(C)S(C)(=O)=O)cc4cccnc34)c2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-{3′-[6-(1-methanesulfonyl-1-methyl-ethyl)quinolin-8-yl]-biphenyl-3-yl}-ethanone from Step 1 (1.0 eq.) in THF (0.1M) was added CeCl3 (1.1 eq.). The mixture was put in an ultrasonic bath for 15 min, cooled to −78° C. then phenyl magnesium bromide was added (5.0 eq.). The final mixture was stirred for 12 h at −20° C., poured in NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 9:1 to 1:9 over 20 min) afforded the title compound as a white solid. 1H NMR (400 MHz, acetone-d6): δ 8.91 (dd, 1H), 8.46 (dd, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 7.97 (d, 1H), 7.86 (d, 1H), 7.68 (dd, 1H), 7.64 (dd, 1H), 7.59–7.50 (m, 5H), 7.48 (d, 1H), 7.39 (t, 1H), 7.27 (t, 2H), 7.16 (t, 1H), 4.73 (s, 1H), 2.72 (s, 3H), 1.99 (s, 6H), 1.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17])=[CH:6]N(C)C)[CH3:2].S(O)(O)(=O)=O.[NH2:25][C:26](=[NH:28])[SH:27].[CH3:29]C([O-])=O.[Na+].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[N:28][C:26]([S:27][CH3:29])=[N:25][CH:6]=1)=[O:19])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: N=C(N)S
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(SC)nc1-c1ccccc1F
Temperature: 85 °C

Procedure:
3-Dimethylamino-2-(2-fluoro-benzoyl)-acrylic acid ethyl ester was dissolved in DMF (100 mL). To the solution was added isothiourea sulfate (18.92 g, 68.0 mmol) and NaOAc (23.24 g, 0.28 mol). The reaction mixture was heated at 80-90° C. overnight. Water was added to the cooled solution. The product was extracted with EtOAc (3×100 mL). The combined organic layers were washed with a saturated aqueous NaHCO3 solution and water, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (1 L silica, EtOAc) to give 4-(2-fluoro-phenyl)-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester as a yellow oil (11.86 g, 40.6 mmol, 60% over 2 steps).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(OC(=O)C)(=O)C.[CH3:19][C:20]([CH3:22])=O>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:20](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])([CH3:22])[CH3:19]
Reactant: CC(C)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C
Yield: 44.7 %

Procedure:
A reaction mixture of 200 g (1.25 mol) of diethyl malonate, 159.51 g (1.56 mol) of acetic anhydride, 108.9 g (1.87 mol) of acetone, and 25.5 g (0.187 mol) of zinc chloride placed in a 1000 ml round bottom flask was allowed to reflux for 20 hours. The reaction mixture was cooled, diluted with 200 ml of benzene, and the resulting mixture was washed with water (4×250 ml). The combined aqueous layer was extracted with benzene (2×50 ml) and the organic layers were combined. After removing benzene in vacuo, the mixture was distilled twice (Vigreux distilling column--10") to afford 111.8 g (44.7%--crude) of diethyl isopropylidenemalonate contains a trace of diethyl malonate), b.p. 80° C./0.5 mm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-tert-butoxycarbonyl-4-piperidone (200 g, 1.01 mol) in tetrahydrofuran (THF) (1500 ml) was added 4-hydroxypiperidine (78.1 g, 0.77 mol). The resultant slurry was stirred for 30 minutes before cooling the reaction mixture with ice/water, acetic acid (47 ml) is then added (exotherm) which caused precipitation. The slurry was allowed to warm to room temperature before the addition of sodium triacetoxyborohydride (236 g, 1.12 mol) which was washed in with THF (500 ml). The resultant slurry was stirred overnight at room temperature. To the reaction mixture was added water (2000 ml) to give a solution. The solution was then extracted with diethyl ether (3×1800 ml). The aqueous phase was basified with 10% aq NaOH (950 ml) and extracted with dichloromethane (DCM) (3×1500 ml). The combined DCM layers are dried (MgSO4), filtered and the solvent removed to give the sub-titled compound as a yellow viscous oil, (177 g, 81%; MS: (M+H) 285).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:27])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][OH:15])=[CH:9][N:8]([CH2:16][C:17]3[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=3)[C:6]=2[N:7]=1.N1C=NN=N1.C(N(C(C)C)[P:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])(C)C.OO.C([O-])(O)=[O:54].[Na+]>C1COCC1.CCOC(C)=O>[P:37]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])([O:15][CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:27])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:16][C:17]2[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[C:20]([CH3:26])=[CH:19][N:18]=2)[CH:9]=1)=[O:54]
Reactant: O=C([O-])O
Reactant: COc1c(C)cnc(Cn2cc(C#CCCO)c3c(Cl)nc(N)nc32)c1C
Reactant: CC(C)N(C(C)C)P(OC(C)(C)C)OC(C)(C)C
Agent: OO
Agent: [Na+]
Agent: c1nnn[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1c(C)cnc(Cn2cc(C#CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Temperature: 0 °C

Procedure:
A solution of 4-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-but-3-yn-1-ol (see example 2) (4.0 g) and 1-H-tetrazole (0.45 M in acetonitrile, 70 mL) in THF (160 mL) was treated with di-tert-butyl diisopropylphosphoramidite (16.4 mL) at rt for 2 h. The solution was cooled to 0° C. and treated with 30% aqueous H2O2 (11 mL) for 30 min. Work-up (EtOAc, aq. NaHCO3) and reverse-phase preparative HPLC gave the title compound, as a solid. HPLC Rt=6.13 min.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7]1[CH2:11][CH:10]=[CH:9][CH:8]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[C@@H:9]12[CH2:10][C@H:11]([CH:7]=[CH:8]1)[C@@H:3]1[C@@H:2]2[C:1](=[O:6])[CH2:5][CH2:4]1
Reactant: C1=CCC=C1
Reactant: O=C1C=CCC1
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: O=C1CC[C@H]2[C@H]1[C@H]1C=C[C@H]2C1
Yield: 81 %

Procedure:
Prepared according to general procedure A from 2-cyclopenten-1-one (50 μL, 0.60 mmol), cyclopentadiene (74 μL, 0.90 mmol), 70% aqueous perchloric acid (10.3 μL, 0.12 mmol) and (2S, 5S)-5-benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (32.4 mg, 0.12 mmol) in water (150 μL) for 12 hours at 0° C. Purification by silica gel chromatography (5:1 pentane:ether) provided the title compound as a volatile white powder in 81% yield (72 mg, 0.49 mmol); 15:1 endo:exo, endo 48% ee. IR (film) 3058, 2964, 2941, 2868, 1730, 1475, 1402, 1341, 1318, 1225, 1172, 1129, 1090, 1040, 936.0, 902.3, 840.8, 804.2, 732.8 cm−1; 1H NMR (300 MHz, CDCl3) δ 6.22 (dd, J=5.7, 2.7 Hz, 1H, CH═CH), 6.11 (dd, J=5.7, 3.0 Hz, 1H, CH═CH), 3.19 (m, 1H, CHCH═CH), 3.00 (m, 1H, CHCH═CH), 2.97 (m, 1H, CHCO), 2.85 (m, 1H, C(H)HCO), 2.02 (m, 4H, CHCH2CH2, C(H)HCO, and CHCH2CH), 1.48 (m, 2H, CH2CH2CO); 13C NMR (75 MHz, CDCl 3) δ 222.6, 136.3, 135.0, 54.7, 52.6, 47.8, 47.4, 41.6, 40.9, 23.1; HRMS (CI) exact mass calc'd for (C10H12O) requires m/z 148.0888, found m/z 148.0887. [α]D+122.3 (c=1.0, CHCl3). Product ratios were determined by GLC analysis (140° C., 23 psi); (1R, 2R, 6R, 7R) endo isomer tr=7.1 min, and (1S, 2S, 6S, 7S) endo isomer tr=6.7 min, exo isomers tr=6.1 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C1(C)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[Cl:44][C:45]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:46]=1[C:47](Cl)=[O:48]>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][N:8]([C:47](=[O:48])[C:46]3[C:45]([Cl:44])=[CH:53][CH:52]=[CH:51][C:50]=3[Cl:54])[C:5]2=[N:6][CH:7]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.9 %

Procedure:
Into a reaction flask under nitrogen, propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (9, 8.40 g, 18.3 mmol) is combined with 100 mL of toluene, 4-dimethylaminopyridine (447 mg, 3.7 mmol), diisopropylethylamine (4.74 g, 36.7 mmol) and 2,6-dichloro-benzoyl chloride (10, 4.34 g, 20.7 mmol). The reaction is stirred at room temperature overnight, then diluted with 300 mL of dichloromethane and washed with 200 mL of saturated aqueous sodium bicarbonate, then 200 mL of brine. The organic layer is dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with a gradient of ethyl acetate:hexane. Appropriate fractions are combined to provide crude material that is further purified with additional chromatography, eluting with 1:1 hexane:dichloromethane up to 100% dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (11, 4.15 g, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2Cl.[O:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:5]2[NH:24][CH:21]1[CH2:22][CH2:23][O:18][CH2:19][CH2:20]1
Reactant: NC1CCOCC1
Reactant: CCOC(=O)c1cnc2ccc(Br)cc2c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Temperature: 80 °C
Reaction time: 18.5 h
Yield: 96.9 %

Procedure:
On a larger scale, ethyl 6-bromo-4-chloroquinoline-3-carboxylate (2196 g, (1976 g active), 6.28 mol) was charged to the vessel with DMA (16 L). Tetrahydro-2H-pyran-4-amine (1224 g, 12.10 mol) was added over 10 minutes with an observed exotherm of 21-27° C. DIPEA (3.5 L, 20.09 mol) was added with no observed exotherm. The mixture was heated to 75-85° C. and the resulting solution stirred for 18.5 h at 80° C. HPLC indicated consumption of starting material and 99.2% product. The reaction was cooled to 50° C. and then poured into water (50 L). The resulting suspension was stirred for 2 h at r.t. and the solids isolated by filtration, washing with water (8 L then 2×4 L). The solid was dried under vacuum at 40° C. for 55 h to give 2307 g of desired material. Analytical data was consistent with that obtained from previous batches.
Reaction SMILES: [O:1]=O.[C:3]([O:6][CH:7]([CH:12]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1)C(Cl)(Cl)Cl)(=O)C.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[Na]>CO.Cl>[CH:12]1([C:7]([O:6][CH3:3])=[O:1])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: O=O
Reactant: CC(=O)OC(C1C=CCCCCCCCCC1)C(Cl)(Cl)Cl
Agent: Cl
Agent: [Na]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CO
Solvent: O
Product: COC(=O)C1C=CCCCCCCCCC1
Yield: 56 %

Procedure:
A stream of dry oxygen was passed through a stirred solution (heated at 30°-35° C.) of 1-(2-cyclododecen-1-yl)-2,2,2-trichloroethyl acetate (12 g; 35 m. moles) in methanol (10 ml) and a solution of cupric chloride dihydrate (0.19 g; 1.1 m. moles) and 1,10-phenanthroline hydrate (0.56 g; 2.85 m. moles) in methanol (45 ml) in which sodium (1.39 g; 6.0 m. moles) had been dissolved was added portionwise over a period of 225 minutes. The mixture was then diluted with dilute hydrochloric acid (100 ml), extracted with ether (3×50 ml) and the combined ether extracts were washed with aqueous sodium carbonate solution (50 ml) and water (50 ml). The dried (MgSO4) extract was evaporated and the crude product (4.7 g) distilled to give methyl 2-cyclododecene-1-carboxylate (3.9 g; 56%), b.p. 90°-110° C./0.1 mm. G.L.C. analysis indicated a purity of 85%.
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].C1CCN2C(=NCCC2)CC1.[Cl:17][C:18]1[CH:19]=[C:20]([O:25][C:26]2[C:41]([F:42])=[CH:40][C:29]([C:30](OC3C=CC(C)=CC=3)=[O:31])=[C:28]([F:43])[CH:27]=2)[CH:21]=[N:22][C:23]=1[F:24]>CC#N.CCOC(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([O:25][C:26]2[C:41]([F:42])=[CH:40][C:29]([C:30]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:31])=[C:28]([F:43])[CH:27]=2)[CH:21]=[N:22][C:23]=1[F:24]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(F)c(Cl)c3)cc2F)cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1cc(F)c(Oc2cnc(F)c(Cl)c2)cc1F
Temperature: 45 °C
Yield: 36.1 %

Procedure:
Methanesulfonamide (52.0 mg, 0.547 mmol) was suspended in MeCN (3 mL) in a sealed vial. 2,3,4,6,7,8,9,10-Octahydropyrimidol[1,2-a]azepine (0.085 mL, 0.57 mmol) was added followed by 4-methylphenyl 4-[(5-chloro-6-fluoropyridin-3-yl)oxy]-2,5-difluorobenzoate (Preparation 67, 215.0 mg, 0.546 mmol). The mixture was heated at 45° C. for 2 hours. The reaction mixture was diluted in EtOAc (15 mL), then washed with 10% aqueous citric acid solution (2×15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was partitioned between DCM (10 mL) and water (10 mL). The organic layer was further washed water (2×10 mL) and concentrated in vacuo to yield the title compound as a white solid (75 mg). EtOAc (15 mL) was added to the combined aqueous. The organic layer was then washed with water (3×10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to yield a second batch of the title compound as a white solid (75.0 mg, 35%):
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: OCc1cccc(-c2ccsc2)c1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.2 %

Procedure:
To a stirred solution of 1.0 g (0.005 mol) of 3-(3-thienyl)phenylmethanol and 0.5 g (0.005 mol) of pyridine in 25 mL of methylene chloride was added in one portion 1.2 g (0.005 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of methylene chloride. The reaction mixture was stirred at ambient temperature for 17 hours, then transferred to a separatory funnel, and diluted with 200 mL of methylene chloride. The solution was washed with 200 mL of aqueous 2 N hydrochloric acid, 200 mL of a saturated aqueous solution of sodium chloride, 200 mL of a cold aqueous 2 N solution of sodium hydroxide, and finally, 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to medium pressure liquid chromatography using petroleum ether:ethyl acetate (55:1) as the eluent. The appropriate fractions were combined and subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 0.1 g of 3-(3-thienyl)-phenylmethyl cis-3-(2,2-dichloroetheny)-2,2-dimethylcyclopropanecarboxylate.