Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:35][CH:36]([F:39])[CH2:37]I>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:37][CH:36]([F:39])[F:35])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: FC(F)CI
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: FC(F)Cn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 14.5 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1,1-difluoro-2-iodoethane, 162 was obtained as a light yellow solid (21 mg, 14.5%) over two steps. 1H NMR (500 MHz, CDCl3) δ (ppm) 9.060-9.062 (d, J=1 Hz, 1H), 8.74 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H), 7.61-7.64 (t, J=16 Hz, 1H), 7.26-7.28 (t, J=10.5 Hz, 1H), 6.42-6.44 (d, J=8.5 Hz, 1H), 6.04-6.26 (m, 1H), 4.51-4.57 (m, 2H), 3.89-3.93 (m, 4H), 3.17-3.19 (t, J=11 Hz, 2H), 2.92-2.94 (t, J=11 Hz, 2H), 2.02-2.05 (m, 2H); MS (ESI) m/z: 425 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[C:11](\[CH3:17])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>O.CO.C1COCC1.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[C:11](\[CH3:17])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: CCOC(=O)/C(C)=C/c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 58.9 %

Procedure:
The obtained ethyl 3-(4-nitrophenyl)-2-methylacrylate (3.5 g) was dissolved in a mixed solvent of water (75 ml), methanol (75 ml), and THF (75 ml). Ammonium chloride (3.05 g) and iron powder (4.2 g) were added thereto, and the obtained mixture was stirred at 50° C. for 4 hours. The iron powder was filtered, and the solvent was distilled off under reduced pressure. Methanol was added to the obtained residue, and insoluble substances were filtered off. The filtrate was separated with ethyl acetate and water. The organic layer was washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (3% chloroform/methanol) to obtain Compound 13a (1.8 g, 32%) as an orange liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[NH:6].[Cl:11][C:12]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:13]=1[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17]>>[NH2:19][CH2:18][C:15]1[C:16]([NH2:17])=[N:6][C:5]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)=[N:7][C:14]=1[C:13]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:12]=1[Cl:11]
Reactant: Cc1cccc(C(=N)N)c1
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Product: Cc1cccc(-c2nc(N)c(CN)c(-c3ccc(Cl)cc3Cl)n2)c1

Procedure:
The title compound, MS: m/e=359.1 (M+H+), was prepared from 3-methyl-benzamidine and 2-(2,4-dichloro-benzylidene)-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.C[CH:9]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17]C=1)[C@@H:10](C(O)=O)[NH2:11].C1C(C=O)=CC2OCOC=2C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:2]1[C:3]2[NH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:15]=2[CH:9]=[CH:10][N:11]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(c1c[nH]c2ccccc12)[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc2c(c1)[nH]c1cnccc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (0.62 mL, 8.11 mmol) was added to a mixture of Intermediate 13a (950 mg, 3.86 mmol) and piperonal (695 mg, 4.63 mmol) in CH2Cl2. (25 mL) at 0° C. under a nitrogen blanket, after which the mixture was warmed to room temperature stirred for 24 hours. The reaction mixture was diluted with CH2Cl2 (50 mL) and neutralized with saturated NaHCO3 solution (10 mL). The organic layer was washed with water (10 mL) and brine (15 mL), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography, eluting with CH2Cl2/EtOAc (10:1), to afford β-carboline Intermediate 18 as an inseparable mixture of cis and trans isomers, and was used for the next step without further purification (950 mg, 65%): TLC Rf (10:1 CH2Cl2/EtOAc)=0.40.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH:7]([CH3:25])[N:8](C(OCC)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:27]=[CH:26][C:5]2[CH2:6][CH:7]([CH3:25])[NH:8][N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: CCOC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Br)ccc2CC1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(Br)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Yield: 92.3 %

Procedure:
5.20 g (12 mmoles) of 8-bromo-3-ethoxycarbonyl-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine (prepared in Example 32) are boiled in 104 ml of methanol with 6 ml of 10N sodium hydroxide solution for 2 hours. After cooling, the reaction mixture is diluted with 104 ml of water, and the precipitated crystals are filtered. Thus, 3.99 g (92%) of the title compound are obtained. M.p.: 125°-130° C.
Reaction SMILES: [N+:1]([O:4][C@H:5]([CH2:16][O:17][N+:18]([O-:20])=[O:19])[CH2:6][CH2:7][CH2:8][C:9]([O:11]C(C)(C)C)=[O:10])([O-:3])=[O:2]>C(Cl)Cl>[N+:1]([O:4][C@H:5]([CH2:16][O:17][N+:18]([O-:20])=[O:19])[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl 5,6-di(nitrooxy)hexanoate (12.41 g, 42.155 mmol) in DCM (47 mL) cooled to 0° C. under N2, boron trifluoride diethyl ether complex (5.82 mL, 46.37 mmol) was added. The reaction mixture was stirred at 0° C. for 10 minutes and at rt for 3 hrs. The solution was washed with brine, the organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude brown oil was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[Cl:25][CH2:26][C:27](Cl)=[O:28].CCN(CC)CC>C1COCC1>[Cl:25][CH2:26][C:27]([NH:24][C:8]1[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])=[N:10][C:11]([CH3:13])=[CH:12][C:7]=1[O:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:28]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1NC(=O)CCl

Procedure:
The title compound was prepared by acylation of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with chloroacetyl chloride, NEt3 in THF at room temperature. A tan solid was isolated, mp. 79–82° C. Anal. For C22H30ClN3O2 calc. C, 65.41; H, 7.49; N, 10.40; found: C, 65.56; H, 7.62; N, 10.98.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5](O)(=O)[CH3:6].[NH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([F:20])=[CH:17][CH:18]=2)[N:13]=[CH:12][C:11]=1[NH:21]C(=N)C(Cl)(Cl)Cl>C(O)C>[CH2:5]([O:3][C:1]([C:2]1[NH:9][C:10]2[C:19]3[CH:18]=[CH:17][C:16]([F:20])=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:21]=1)=[O:4])[CH3:6]
Reactant: N=C(Nc1cnc2cc(F)ccc2c1N)C(Cl)(Cl)Cl
Reactant: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nc2cnc3cc(F)ccc3c2[nH]1
Yield: 58.5 %

Procedure:
A solution of 1.15 g of 4-amino-7-fluoro-3-(trichloroacetimidoylamino)quinoline diacetate (VIII-1) in 120 ml of ethanol was heated under reflux for two hours. The reaction mixture was concentrated under reduced pressure, and the residue was added to ice-water. After being basified with 2N aqueous ammonia, the mixture was extracted with chloroform. The extract was washed with water and brine, and then dried. The chloroform was removed by evaporation. The residue was chromatographed on a column of silica gel with chloroform-methanol (100:1 v/v), whereby 395 mg (yield: 59%) of the titled compound (I e-1) was obtained as crystals. These were recrystallized from chloroform-ethanol to give colorless crystals melting at 238°~240° C. (d).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][C:14]=2[N+:16]([O-])=O)[C@H:9]([N:20]([CH2:25][C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([Cl:19])=[CH:13][C:14]=2[NH2:16])[C@H:9]([N:20]([CH2:25][C:26]2[CH:27]=[C:28]([C:36]([F:37])([F:38])[F:39])[CH:29]=[C:30]([C:32]([F:35])([F:33])[F:34])[CH:31]=2)[C:21]([O:23][CH3:24])=[O:22])[CH2:8][C@@H:7]1[CH3:40])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2c(cc(Cl)cc2[N+](=O)[O-])[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1c2c(N)cc(Cl)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OC)C[C@@H]1C
Reaction time: 0.25 h
Yield: 54.4 %

Procedure:
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-8-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (Example 107) (0.747 g, 1.25 mmol), ethanol (20 mL), and 10% palladium on carbon (0.40 g) were combined and agitated under 36 psi of H2 on a Parr shaker for 2 h and 15 min. The mixture was then filtered through a bed of Celite®. The Celite® was washed with ethanol, and the filtrate was concentrated in vacuo. Purification by silica gel chromatography using 30-100% ethyl acetate/hexanes as eluent afforded 0.386 g (54%) of cis-8-amino-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-6-chloro-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m/z 568 (M++H); 1H NMR (CDCl3) δ 7.8 (bs, 1H), 7.7 (bs, 1H), 7.65 (bs, 1H), 6.7 (bs, 1H), 6.38 (bs, 1H), 3.78 (s, 3H), and 0.161 g (24%) of cis-8-amino-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester MS m/z 534 (M++H); 1H NMR (CDCl3) δ 7.79 (bs, 1H), 7.7 (bs, 1H), 7.65 (bs, 1H), 7.02 (bt, 1H), 6.72 (bs, 1H), 6.4 (bd, 1H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C[O:26][C:27]([C:29]1([CH3:32])[CH2:31][CH2:30]1)=O>>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:27]([C:29]3([CH3:32])[CH2:31][CH2:30]3)([OH:26])[O:22][N:21]=2)=[CH:9][CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)C1(C)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(Cc2ccccc2)=NO)cc1
Product: CC1(C2(O)ON=C(c3ccc(O[Si](C)(C)C(C)(C)C)cc3)C2c2ccccc2)CC1

Procedure:
The synthetic intermediate 3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-5-(1-methyl-cyclopropyl)-4-phenyl -4,5-dihydro-isoxazol-5-ol (0.833 g) is prepared from Example 1, Compound B and 1-methyl-cyclopropanecarboxylic acid methyl ester by the general method described in Step A of Example 35.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[C:4]([CH3:14])[C:3]=1[C:15]#[N:16].[C:17]([N:25]=[C:26]=[O:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCOCC1.CCOC(C)=O>[C:17]([NH:25][C:26](=[O:27])[NH:1][C:2]1[S:6][C:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[C:4]([CH3:14])[C:3]=1[C:15]#[N:16])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)sc(N)c1C#N
Reactant: O=C=NC(=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c(C(=O)OC(C)(C)C)sc(NC(=O)NC(=O)c2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
To a solution of tert-butyl 5-amino-4-cyano-3-methylthiophene-2-carboxylate (example 64b) (16 g, 67.14 mmol) in dioxane (200 mL), was added benzoyl isocyanate (10 g, 67.14 mmol). The reaction mixture was stirred at rt overnight, and upon completion was diluted with EtOAc, washed with NaHCO3, water, brine, dried over MgSO4, filtered and concentrated to yield tert-butyl 5-(3-benzoylureido)-4-cyano-3-methylthiophene-2-carboxylate (21.78 g, 84%) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 1.54 (s, 9H), 3.58 (s, 3H), 7.58 (t, J=7.5 Hz, 2H), 7.71 (t, J=7.5 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 8.05 (d, J=7.5 Hz, 2H), 12.25 (br s, 1H).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:41])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4Br)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:30])[C:12]=2[C@H:31]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[C:32]([O:34][CH3:35])=[O:33])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(CC)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)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]>[C:37]([O:36][C@@H:31]([C:12]1[C:13]([CH3:30])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:41])([O:4][CH2:1][CH:2]=[CH:3][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH2:22][O:21][CH2:20]3)[CH2:6][CH2:7]1)[C:32]([O:34][CH3:35])=[O:33])([CH3:40])([CH3:39])[CH3:38]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(COCc4ccccc4Br)nn23)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCC=Cc1ccccc1COC3
Temperature: 120 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-bromobenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.025 g, 0.040 mmol) in acetonitrile (1 ml) in a pressure tube were added Et3N (0.055 ml, 0.397 mmol), triphenylphosphine (3.12 mg, 0.012 mmol) and tris(dibenzylideneacetone)dipalladium (0) (3.64 mg, 3.97 μmol). The tube was sealed and the mixture was stirred at 120° C. After 18 h, the dark mixture was cooled and concentrated. The brown residue was purified by flash chromatography (Biotage; 0%-60% EtOAc/hexane; 20 CV) to afford the title compound as mixture of cis- and trans-isomers (16.9 mg, 0.031 mmol, 78% yield) as a pale yellow oil. LCMS (M+H) calcd for C31H41N4O5: 549.30. found: 549.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Li].Cl[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([O:31]C)=[O:30])=[N:27][CH:28]=1)(=[O:22])=[O:21].[OH-].[Na+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1)(=[O:21])=[O:22]
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cn1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(C(=O)O)nc2)c(OC)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 6, 961 mg, 3.84 mmol, 1.0 eq) was suspended in THF (10 ml) and stirred at −78° C. for 10 minutes. 1,1,1,3,3,3-Hexanemethyldisilazane lithium salt (LiHMDS, 1M in THF, 4.2 ml, 4.2 mmol, 1.1 eq) was added dropwise maintaining the temperature below −70° C. and the reaction mixture stirred for a further 30 minutes. A solution of methyl 5-(chlorosulfonyl)pyridine-2-carboxylate (Preparation 16, 1 g, 3.8 mmol, 1 eq) in THF (5 ml) was added dropwise maintaining the reaction temperature below −72° C. and the reaction mixture allowed to warm to room temperature for 2 hours. The reaction mixture was diluted with water (10 ml), extracted into ethyl acetate (5 ml), dried over sodium sulphate, filtered and evaporated in vacuo. The crude material was dissolved in dioxane (5 ml), a solution of sodium hydroxide (311 mg, 7.77 mmol, 2 eq) in water (2 ml) was added and the reaction mixture stirred at room temperature for 30 minutes. The MeOH was evaporated and the remaining aqueous solution washed with ethyl acetate (10 ml). Brine (10 ml) was added to the aqueous phase and the solution extracted with ethyl acetate (10 ml). A precipitate formed in the organic phase which was collected by filtration to yield the title compound as a white solid (415 mg, 0.95 mmol, 25%).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C@@H:16]2[CH2:18][C@H:17]2[NH:19]C(=O)OC(C)(C)C)=[CH:12][C:11]=1[CH3:27])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].COC1CCCC1>>[ClH:28].[NH2:19][C@@H:17]1[CH2:18][C@H:16]1[C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:11]([CH3:27])[CH:12]=1
Reactant: Cc1cc([C@@H]2C[C@H]2NC(=O)OC(C)(C)C)ccc1NC(=O)c1ccccc1
Agent: Cl
Solvent: COC1CCCC1
Product: Cc1cc([C@@H]2C[C@H]2N)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl {trans-2-[4-(benzoylamino)-3-methylphenyl]cyclopropyl}carbamate (125.8 mg) was dissolved in 4N hydrochloric acid/cyclopentyl methyl ether solution (1.5 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was evaporated under reduced pressure to give the title compound (95.9 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]([CH3:14])[C:11](=[O:15])[NH:10][C:9]=2[CH:16]=1)=[O:4].[H-].[Na+].[CH2:19](I)[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:10]1[C:9]2[CH:16]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][C:8]=2[O:13][CH:12]([CH3:14])[C:11]1=[O:15])[CH3:20]
Reactant: CCI
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)Oc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of 6-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.2 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.5 g) and ethyl iodide (1.8 g) and the mixture was stirred at room temperature for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:1 (v/v)] to give 4-ethyl-6-methoxycarbonyl-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (2.0 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)(C)C>[C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)([C:4]([OH:5])=[O:3])[CH2:7]1)([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13]
Reactant: CCOC(=O)C1(Cc2ccc(Cl)cc2)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ccc(Cl)cc2)(C(=O)O)C1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A suspension of Ethyl-3-(4-chlorobenzyl)-N-Boc-piperidin-3-caroxylate (36.4 g, 0.105 mol) in isopropyl alcohol (300 mL) was treated with 10N NaOH (300 mL). The mixture was heated at reflux for 48 hours. The reaction was cooled to room temperature and carefully neutralized by pouting over 1 L of crashed ice and adding 6 N HCl until pH 3. The mixture was then extracted with ethyl acetate (3×500 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure to give 31 g of the product. 1H NMR CDCl3 δ 10.18 (br s), 7.26 (d, J=8.5 Hz, 2H), 7.04 (d, J=8.5 Hz, 2H), 3.95 (m, 1H), 3.6 (m, 1H), 3.2 (m, 2H), 2.90 (d, J=12 Hz, 1H), 2.78 (d, J=12 Hz, 1H), 2.00 (m, 1H), 1.75-1.30 (m, 3H), 1.44 (s, 9H).
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>CC(C)=O>[CH2:16]([O:15][C:7]([CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C@H:3]1[CH2:4][CH2:5][C:1](=[O:6])[CH2:2]1)=[O:14])[CH3:17]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C1C=CCC1
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)[C@H]1CCC(=O)C1
Temperature: 40 °C
Reaction time: 24 h
Yield: 95.3 %

Procedure:
Under an atmosphere of argon, 24.0 mg (0.04 mmol, S/C=50) of RuH[(R,R)-Tsdpen] (1,3,5-trimethylbenzene), 168 μL (2.0 mmol) of 2-cyclopentenone, 304 μL (2.0 mmol) of diethyl malonate, and 2 mL of acetone were placed in a 20 mL Schlenk tube and stirred at 40° C. for 24 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 462 mg (95% yield) of the title compound. After this was converted into an ethylene ketal derivative by the same procedure as in Example 3, the optical purity was measured by HPLC (CHIRALCEL OD manufactured by Daicel Chemical Industries, Ltd., hexane:2-propanol=97: 3, flow rate 0.5 mL/min, detection at 210 nm) and it was found to be 91% ee.
Reaction SMILES: CN(/[CH:4]=[C:5]1/[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]/1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:24]=[C:25]([NH2:27])[N:26]=[CH:4][C:5]=2[CH2:14]1
Reactant: N=C(N)N
Reactant: CN(C)/C=C1\C[C@@H](c2ccccc2F)c2ccccc2C1=O
Agent: Cl
Product: Nc1ncc2c(n1)-c1ccccc1[C@H](c1ccccc1F)C2

Procedure:
This was synthesized by using (R,E)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and guanidine hydrochloride as described in general procedure 1 to afford the desired product as hydrochloride salt. M.p.=154-155° C. 1H NMR 400 MHz (DMSO-d6) δ 8.26-8.24 (m, 1 H), 8.08 (s, 1 H), 7.46-7.39 (m, 2 H), 7.31-7.20 (m, 2 H), 7.05-7.00 (m, 2 H), 6.80-6.76 (m, 1 H), 6.51 (s, 2 H), 4.59 (t, J=6.8 Hz, 1 H), 3.11-3.2.96 (m, 2 H). LCMS m/e 292 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:8]([OH:10])=[O:9])=[O:5].C(N(CC)CC)C.[C:42]([O:48][CH2:49]Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>CCOC(C)=O>[C:42]([O:48][CH2:49][O:9][C:8](=[O:10])[CH:7]([NH:6][C:4](=[O:5])[C:3]1[C:30]([Cl:34])=[CH:31][CH:32]=[CH:33][C:2]=1[Cl:1])[CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]
Reactant: O=C(NC(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)C(=O)O)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCOC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To 2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoic acid 38 (534 mg) are added 195 μl of triethylamine and, after 15 minutes, 290 μl of chloromethyl pivalate. The solution is stirred at RT overnight and then poured in AcOEt. The organic phases are washed with water and brine, dried over MgSO4 and concentrated. The resulting residue is purified over silica gel using CH2Cl2/C2H5OH 99/1 as eluent to give ({2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoyl}oxy)methyl pivalate 129.