Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CO[C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=3)[N:7]([CH2:19][C:20]([O:22]C)=[O:21])[C:6]2=[O:24])[O:4]C1.C(O)(C(F)(F)F)=O>O1CCOCC1.O>[CH3:18][S:15]([NH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([OH:22])=[O:21])[C:6](=[O:24])[C:5]2=[O:4])(=[O:16])=[O:17]
Reactant: COC(=O)CN1C(=O)C2(OCC(C)(C)CO2)c2cc(NS(C)(=O)=O)ccc21
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)C(=O)N2CC(=O)O
Temperature: 80 °C
Reaction time: 24 h
Yield: 95.4 %

Procedure:
A solution of methyl 2-(5,5-dimethyl-5′-(methylsulfonamido)-2′-oxospiro[[1,3]dioxane-2,3′-indoline]-1′-yl)acetate (200 mg, 0.502 mmol) in dioxane/water 1:1 (7 ml) and TFA (0.193 ml, 2.510 mmol) was stirred at 80° C. overnight. TFA (0.271 ml, 3.51 mmol) was freshly added and stirring at 80° C. was continued for 24 hours. Then TFA (0.155 ml, 2.008 mmol) was freshly added and stirring at 80° C. was continued for additional 48 hours. The volatiles were removed under vacuum and the crude was purified by flash chromatography on silica gel (DCM:MeOH from 99.5:0.5 to 7:3+0.5% AcOH), affording 2-(5-(methylsulfonamido)-2,3-dioxoindolin-1-yl)acetic acid (143 mg, 0.479 mmol, 96% yield). MS/ESI+ 298.9 [MH]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52](O)=[O:53])[CH:46]([O:55][CH3:56])[CH2:45]2)[CH:7]([CH3:58])[CH2:6][CH2:5][C:4]1=[O:59])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:94][CH2:95][CH2:96][C:97]1[C:105]2[C:100](=[CH:101][CH:102]=[CH:103][CH:104]=2)[NH:99][CH:98]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:57])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][C:52]([NH:94][CH2:95][CH2:96][C:97]3[C:105]4[C:100](=[CH:101][CH:102]=[CH:103][CH:104]=4)[NH:99][CH:98]=3)=[O:53])[CH:46]([O:55][CH3:56])[CH2:45]2)[CH:7]([CH3:58])[CH2:6][CH2:5][C:4]1=[O:59])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: NCCc1c[nH]c2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(=O)NCCc4c[nH]c5ccccc45)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Reaction time: 0.17 h
Yield: 49.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-carboxymethyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,-10,16-tetraone (13 mg) (STEP 12D) in methylene chloride (150 μl) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (10.3 mg) followed by triethylamine (4.3 μl). After 10 minutes, tryptamine (5 mg) was added to the reaction mixture and stirred for 1 hour. The mixture was diluted with ethyl acetate and washed with 1N HCl, water, saturated sodium bicarbonate and brine, respectively. The organic portion was dried over magnesium sulfate and purified by flash chromatography on silica gel (ethyl acetate:hexane (1:1)+1% methanol) to give the title compound (7.5 mg). MASS (FAB) 983 (M+Li); partial 1H NMR δ: 8.32 (brs, 1H); 7.89 (m, 1H); 7.58 (d, J=8 Hz 1H); 7.31 (m, 1H); 7.10 (m, 3H); 4.51 (brd, J=3 Hz, 1H); 4.41 (brd, J=14 Hz, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24].[CH2:25]([O:27][P:28]([O:32]CC)[O:29][CH2:30][CH3:31])[CH3:26]>C(OCC)(=O)C>[O:24]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22](=[O:23])[N:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:28](=[O:32])([O:29][CH2:30][CH3:31])[O:27][CH2:25][CH3:26]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCCCCBr
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(CCCCCCCCCCCCN1C(=O)c2ccccc2C1=O)OCC
Temperature: 135 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
2-(12-bromododecyl)isoindoline-1,3-dione (9.30 g, 23.6 mmol) was combined with triethylphosphite (11.76 g, 70.7 mmol) in a round bottom flask and the mixture heated and stirred at 135° C. for 16 hours. The reaction mixture was then put under hi-vacuum at 90° C. for 4 hours. The product was then obtained as a clear oil after column chromatography in ethyl acetate. (8.96 g, 84% yield). 1H NMR (400.14 MHz, CDCl3) δ 7.80 (dd, J=5.43, 3.04 Hz, 2H), 7.67 (dd, J=5.47, 3.05 Hz, 2H), 4.08-4.02 (m, 4H), 3.63 (t, J=7.33 Hz, 2H), 1.73-1.45 (m, 6H), 1.32-1.11 (m, 22H). 13C{1H} NMR (100.62 MHz, CDCl3) δ 168.4 (2C), 133.7 (2C), 132.1 (2C), 123.0 (2C), 61.30 (d, J=6.5 Hz, 2C), 37.96, 30.51, (d, J=17.0 Hz), 29.41 (2C), 29.35, 29.25, 29.07, 28.98, 28.49, 26.75, 25.55 (d, J=140.1 Hz), 22.29 (d, J=5.0 Hz), 16.39 (d, J=6.1 Hz, 2C). 31P{1H} NMR (161.97 MHz, CDCl3): δ 33.38. MS (ESI, m/z): 452.235 (M+, 100%). Exact mass calculated (found) for [M+H]+, m/z): 452.256039 (452.254800). Analysis calculated (found) %: C, 63.84 (63.41), H, 8.48 (8.53).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=4[F:40])[CH:31]=3)[N:26]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:25]=2)[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[F:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([F:40])[C:33]=1[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)[N:25]=[C:24]2[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: Fc1cccc(F)c1-c1ccc2c(c1)c(-c1ccnc(Cl)n1)nn2C1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nccc(-c3nn(C4CCCCO4)c4ccc(-c5c(F)cccc5F)cc34)n2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.9 %

Procedure:
To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (0.28 g, 1.32 mmol) in DMF (10 mL) was treated with NaH (0.056 g, 2.34 mmol) and stirred for 15 min. The reaction mixture was cooled to 0° C. and 3-(2-chloropyrimidin-4-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.17 mmol) was added. The resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to obtain (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.2 g, 18%). MS (ESI, pos. ion) m/z: 591.1 (M+1). To a solution of (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.3 g, 0.5 mmol) in EtOAc (10 mL) was added EtOAc-HCl (10 mL) and stirred at RT for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse-phase preparative HPLC (using a AG/PP/C18-15/021 column, eluting with gradient, A: 5% TFE+0.01% TFA in Water; B: ACN). The title compound was obtained. MS (ESI, pos. ion) m/z: 407.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[Cl:19]Cl.Cl.N#N>O>[CH:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[C:7]([Cl:19])[CH:6]=1)(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: ClCl
Reactant: Cc1ccc(S(=O)(=O)C(C)C)cc1
Agent: Cl
Agent: N#N
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)C(C)C)cc1Cl
Temperature: 20 °C
Yield: 57.3 %

Procedure:
99.1 g (0.5 mol) of isopropyl 4-methylphenyl sulfone in 180 g of 96% strength sulfuric acid are introduced into a 500 ml glass flask equipped with stirrer, condenser, gas inlet, thermometer and dropping funnel. At 70° C., about 140 g of chlorine are metered in over the course of 6 hours with vigorous stirring. After the reaction is completed, residual hydrogen chloride is eliminated by passing a N2 stream through the flask, 300 g of water are added dropwise and the mixture is allowed to cool to 20° C. in the course of 2 hours with stirring. The mixture is extracted four times each with 200 g of methylene chloride, the combined extracts are washed to neutrality using 5% strength NaHCO3 solution, dried with Na2SO4 and concentrated on a rotary evaporator. 66.7 g of 3-chloro-4-methylphenyl isopropyl sulfone are obtained (yellowish oil, content 94.3% by weight, corresponding to a yield of 54.1%, 1H-NMR (CDCl3): 7.3-7.9 (m, 3H); 3.23 (sp, 6.8 Hz, lH); 2.47 (s); 1.42 d, 6.8 Hz, 6H).
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[N:13][S:14][C:10]=2[C:9]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:7])(C)(C)C.O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:9]1[C:10]2[S:14][N:13]=[CH:12][C:11]=2[CH:15]=[CH:16][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2cnsc2c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 7-(2-fluoro-4-iodo-phenylamino)-benzo[d]isothiazole-6-carboxylic acid tert-butyl ester (710 mg, 1.51 mmol) in DCM (5 mL) were added water (0.15 mL) and TFA (5 mL). The reaction mixture was stirred at room temperature for 1 hour before being concentrated in vacuo. The resultant residue was azeotroped with toluene to give the title compound as a yellow solid (571 mg, 91%). LCMS (method B): RT=3.95 min, [M+H]+=415.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:28])[C@H:10]2[NH:14][C:15]2[S:16][C:17]([C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][N:19]=2)[C:7]=1[C:29]([O:31]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:30])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[C:1]([O:4][CH2:5][C:6]1[CH2:13][S:12][C@H:11]2[N:8]([C:9](=[O:28])[C@H:10]2[NH:14][C:15]2[S:16][C:17]([C:20](=[O:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:18][N:19]=2)[C:7]=1[C:29]([OH:31])=[O:30])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](Nc3ncc(C(=O)c4ccccc4)s3)[C@H]2SC1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](Nc3ncc(C(=O)c4ccccc4)s3)[C@H]2SC1

Procedure:
A 235 mg portion of (6R-trans)-3-[(Acetyloxy)methyl]7-[(5-benzoyl-2-thiazolyl)amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester was reacted with anisole and trifluoroacetic acid in dichloromethane as described in Example 5, giving 143 mg of the desired product as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH2:10][C:11]([OH:13])=O)[C:6]=2[C:14]=1[F:15].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[CH3:18].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC#N.O>[C:29]([C:25]1([C:22]2[CH:21]=[CH:20][C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]3[C:6]4[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[N:9]=[CH:8]3)[CH3:18])=[CH:24][CH:23]=2)[CH2:28][CH2:27][CH2:26]1)#[N:30]
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Reactant: CC(N)c1ccc(C2(C#N)CCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C2(C#N)CCC2)cc1

Procedure:
N-{1-[4-(1-Cyanocyclobutyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide is synthesized according to example 5 by mixing (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (212 mg, 1.00 mmol) prepared according to scheme 2, 1-[4-(1-aminoethyl)phenyl]cyclobutanecarbonitrile (200 mg, 1.00 mmol) prepared according to scheme 9, Et3N (304 mg, 3.00 mmol, 0.418 mL) and HATU (280 mg, 1.00 mmol) in MeCN (10.0 mL). The product is purified by HPLC: Gilson prep pumps, Flow rate: 30 ml/min, Column: Gemini (5μ) 21.2×50 mm, Mobile phase: A=water (10 mM NH4CO3) B=MeCN, (220 mg, 0.558 mmol, 56%). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.39 (d, J=7.03 Hz, 3H) 1.91-2.05 (m, 1 H) 2.16-2.34 (m, 1H) 2.53-2.64 (m, 2H) 2.66-2.78 (m, 2H) 4.87-5.01 (m, 1H) 5.07 (s, 2 H) 7.11-7.31 (m, 1H) 7.33-7.49 (m, 5H) 8.19 (s, 1H) 8.84 (d, J=7.81 Hz, 1H); MS [M+H], calcd: 395.0. found: 395.2.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[NH:8][C:7]=1[Si](CC)(CC)CC)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[F:17][C:15]([F:16])([F:18])[C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C(F)(F)F)cc2c1CCN=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: NCCc1c[nH]c2ccc(C(F)(F)F)cc12

Procedure:
2-(5-(trifluoromethyl)-1H-indol-3-yl)ethanamine was prepared according to method D Step V with 3-(2-azidoethyl)-2-(triethylsilyl)-5-(trifluoromethyl)-1H-indole (0.400 g; 1.09 mmol) and triphenyl phosphine (0.427 g; 1.63 mmol) in methanol (5 mL) and tetrabutylamonium fluoride (3.26 mL, 1M) in THF (stirred for 36 hours).
Reaction SMILES: [CH3:1][C:2]1[N:6](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:5]=[N:4][C:3]=1/[CH:26]=[CH:27]/[C:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[CH3:40])=[O:29].[C:41]([OH:44])(=[O:43])[CH3:42].C1C[O:48]CC1>O>[C:28]([OH:48])(=[O:29])/[CH:30]=[CH:42]\[C:41]([OH:44])=[O:43].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:26][CH2:27][C:28]([C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[CH3:40])=[O:29]
Reactant: C1CCOC1
Reactant: CC(=O)O
Reactant: Cc1ccc2ccccc2c1C(=O)/C=C/c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Solvent: O
Product: Cc1ccc2ccccc2c1C(=O)CCc1nc[nH]c1C
Product: O=C(O)/C=C\C(=O)O

Procedure:
A mixture of (E)-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-1-(2-methyl-1-naphthalenyl)-2-propen-1-one (1.25 g), acetic acid (10 ml), THF (10 ml) and water (10 ml) was heated on a steam bath for 1 h. The mixture was then hydrogenated according to the General Procedure and the resulting filtrate was evaporated in vacuo and partitioned between dichloromethane (3×75 ml) and 0.2N sodium hydroxide (100 ml). The combined organic layers were dried and evaporated in vacuo to leave a foam (1.3 g) which was purified by FCC eluting with System A (94.5:5:0.5) to give the free base of the title compound as an oil. The product of maleic acid formation was triturated with ether to give the title compound (0.78 g), m.p. 108°-109°.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])(=[O:3])[CH3:2].[N:10]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[N:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]>C1(C)C=CC=CC=1>[CH:15]([O:14][C:12]([N:11]([C:4]1([C:1](=[O:3])[CH3:2])[CH2:8][CH2:7][CH2:6][C:5]1=[O:9])[NH:10][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[O:13])([CH3:17])[CH3:16]
Reactant: CC(=O)C1CCCC1=O
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: Cc1ccccc1
Product: CC(=O)C1(N(NC(=O)OC(C)C)C(=O)OC(C)C)CCCC1=O
Reaction time: 18 h
Yield: 96.8 %

Procedure:
To a solution of 2-acetyl-cyclopentanone (13.9 mg, 0.11 mol) and (R,R)-trans-1-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(N,N-dimethylamino)cyclohexyl]thiourea (4.1 mg, 0.01 mmol) in toluene (1 mL) was added diisopropyl azodicarboxylate (21.5 μL, 0.10 mmol) at −78° C. After stirring for 18 hr, the reaction mixture was concentrated. The residue was purified by silica gel column (hexane/ethyl acetate=3/1) to give the title compound (31.8 mg, yield: 97%, optical purity: 77% ee). Colorless oil
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>>[F:1][CH:2]([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([NH:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(C(F)F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cccc(C(F)F)c1
Yield: 56 %

Procedure:
The title compound is prepared in 56% yield (0.53 g, colorless oil) from 1-(3-(difluoromethyl)phenyl)ethanone (0.58 g, 3.41 mmol, Step-1) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: ON=[C:3]1[C:17]2[C:18]3[C:13]([CH:14]=[CH:15][N:16]=2)=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]2[C:4]1=[CH:5][CH:6]=[CH:7]2.[OH-:19].[Na+]>C(O)C.O>[CH:10]1[C:9]2[N:8]3[C:4]([C:3](=[O:19])[C:17]4[C:18]=2[C:13]([CH:14]=[CH:15][N:16]=4)=[CH:12][CH:11]=1)=[CH:5][CH:6]=[CH:7]3
Reactant: ON=c1c2nccc3cccc(c32)n2cccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=c1c2nccc3cccc(c32)n2cccc12

Procedure:
The 7-Imino-7H-indolizino[5,6,7-ij]isoquinoline (110 g.) and N sodium hydroxide solution ( ##SPC14## cc.) in ethanol (4.4 liters) and water (4.4 liters) are heated under reflux for 4 hours. After cooling, 7H-indolizino[5,6,7-ij]isoquinolin-7-one (108.1 g.) is obtained in the form of yellow needles melting at 264° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:15][C@H:9]12)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:19]([O:18][C:16]([N:14]1[CH2:13][C@@H:10]2[C@@H:9]([NH:8][CH2:12][CH2:11]2)[CH2:15]1)=[O:17])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1C[C@H]2CCN[C@H]2C1

Procedure:
The product of Example 1A ((3aR,6aR)-hexahydro-pyrrolo[3,4-b]pyrrole-1,5-dicarboxylic acid 5-benzyl ester 1-tert-butyl ester) (4.5 g, 12.5 mmole), was stirred with a mixture of dichloromethane and trifluoroacetic acid (15 ml/15 ml) for 2 hours. The solvent was removed under reduced pressure, and the residue was basified with saturated sodium bicarbonate, then extracted with dichloromethane (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0.6% ammonium hydroxide and 6% methanol in dichloromethane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.28-7.40 (m, 5H) 5.12 (s, 2H) 3.74-3.87 (m, 1H) 3.53-3.71 (m, 2H) 3.36-3.48 (m, 1H) 3.18-3.32 (m, 1H) 3.01-3.13 (m, 1H) 2.88-3.01 (m, 1H) 2.70-2.83 (m, 1H) 1.87-2.03 (m, 1H) 1.58-1.76 (m, 1H). MS, (M+H)+=247.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Br)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:29]1[CH:30]=[C:25]([CH2:24][OH:23])[CH:26]=[CH:27][CH:28]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:19]([F:22])([F:21])[F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(Br)c(Cc3ccccc3)cnc12
Reactant: OCc1cccc(B(O)O)c1
Product: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (3-benzyl-4-bromo-8-(trifluoromethyl)quinoline in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-(hydroxymethyl)phenylboronic acid in place of phenyl boronic acid; MS (ES) m/z 392.5.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].C(=O)(O[CH:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[CH:17]=[CH2:18])OC.O>C1COCC1.C(Cl)(Cl)Cl>[S:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[CH:16]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])[CH:17]=[CH2:18]
Reactant: COC(=O)CC(=O)OC
Reactant: C=CC(OC(=O)OC)c1cccs1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CC(c1cccs1)C(C(=O)OC)C(=O)OC
Temperature: 60 °C

Procedure:
Cycloheptyl ligand IV (10.2 mg, 0.030 mmol) and Mo(CO)3(EtCN)3 (6.9 mg, 0.020 mmol) were dissolved in 1.0 ml of THF at rt. The reaction mixture was heated at 60° C. for 1 h. After cooling to rt., 1.0 ml of THF solution of sodium dimethylmalonate enolate, prepared from dimethyl malonate (58.0 mg, 0.44 mmol) and sodium hydride (10.2 mg, 0.40 mmol) in tetrahydrofuran, and methyl 1-(2-thienyl)-2-propenyl carbonate were added successively. The reaction mixture was heated at 65° C. for 4.5 h. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, and the solvent was removed under reduced pressure. The ratio of dimethyl 2-(1-thiophene-2-yl-allyl)-malonate and linear compound was determined by 1H NMR (400 MHz) to be 16.0/1. The residue was chromatographed on silica (1/7 ethyl acetate/petroleum ether, Rf=0.3) to yield the mixture of branched and linear compound. (40.3 mg, 78%) [α]D−31.1° (c 1.35, CHCl3); 92% e.e. for major isomer.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][C:19](O)=[O:20])[CH2:13]1.O>C1COCC1>[O:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][CH2:19][OH:20])[CH2:13]1
Reactant: O=C(O)CC1CCCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1CCCOC1
Reaction time: 1 h

Procedure:
A solution of lithium aluminium hydride in Et2O (4.16 ml, 4.16 mmol) was added dropwise to a solution of tetrahydro-2H-pyran-3-ylacetic acid (Tet. Lett. 2003, 44, 6355) (0.6 g, 4.16 mmol) in THF (5 ml) at room temperature under nitrogen. The mixture was stirred for 1 hour and was treated very slowly dropwise with water (1 ml). After the reaction was quenched, aqueous sodium hydroxide (2N, 1 ml) was added and the mixture was stirred for 5 min. The suspension was filtered through Hyflo and evaporated to the title compound as a colourless oil (0.3 g).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH2:41])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]>>[OH:27][CH2:28][C:29]([NH:32][S:33]([C:36]1[S:40][C:39]([NH:41][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[N:38][C:37]=1[CH3:42])(=[O:35])=[O:34])([CH3:31])[CH3:30]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(N)sc1S(=O)(=O)NC(C)(C)CO
Product: Cc1nc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 2-amino-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.3) according to general procedure II. Yellow solid. MS (ISP) 621.0 [(M−H)−]; mp 257° C.