Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:37]=[CH:38][CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:29])[F:31])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([N:43]4[CH2:42][CH2:41][N:40]([C:36]5[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:46])([F:47])[F:32])[CH:35]=5)[CH2:45][CH2:44]4)=[O:24])=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[3-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.99 (M+H+); retention time=1.08 minutes.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([O:14][CH3:15])=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:15][O:14][C:12]([C:9]1([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)=[O:13]
Reactant: COC(=O)C1(c2ccc(OC)cc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: COC(=O)C1(c2ccc(O)cc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of methyl 1-(4-methoxyphenyl)cyclopropanecarboxylate (10.0 g, 48.5 mmol) in dichloromethane (80 mL) was added EtSH (16 mL) under ice-water bath. The mixture was stirred at 0° C. for 20 min before AlCl3 (19.5 g, 0.15 mmol) was added slowly at 0° C. The mixture was stirred at 0° C. for 30 min. The reaction mixture was poured into ice-water, the organic layer was separated, and the aqueous phase was extracted with dichloromethane (50 mL×3). The combined organic layers were washed with H2O, brine, dried over Na2SO4 and evaporated under vacuum to give 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (8.9 g, 95%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.17 (m, 2H), 6.75-6.72 (m, 2H), 5.56 (s, 1H), 3.63 (s, 3H), 1.60-1.57 (m, 2H), 1.17-1.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:15][C:16]([F:27])([F:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([F:27])([F:26])[F:15])[C:11]([CH:12]=[O:13])=[CH:10]2
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc2cc(C=O)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure A using 2-chloro-8-methylquinoline-3-carbaldehyde (2.0 g, 9.73 mmol), 2-(trifluoromethyl)phenylboronic acid (2.032 g, 10.7 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium (562 mg, 5% mmol), and sodium carbonate (5.15 g, 48.6 mol, 5 eq) in MeCN (75 mL) and water (25 mL). After purification, 8-methyl-2-(2-(trifluoromethyl)phenyl)quinoline-3-carbaldehyde was obtained as a white solid. 1H NMR (DMSO-d6) δ ppm 9.93 (1H, s), 9.04 (1H, s), 8.13 (1H, d, J=8.1 Hz), 7.93 (1H, d, J=7.3 Hz), 7.85 (1H, d, J=7.1 Hz), 7.72-7.82 (2H, m), 7.64-7.71 (1H, m), 7.59 (1H, d, J=7.3 Hz), 2.67 (3H, s). Mass Spectrum (ESI) m/e=316.1 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:5][CH:4]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(NC2=NN(Cc3ccccc3)CC2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(Nc2ccn(Cc3ccccc3)n2)cc1

Procedure:
To a stirred solution of the product of step (a) (13.3 g) in dichloromethane (250 ml) was added active manganese dioxide in portions until all traces of starting material had disappeared. The reaction mix was filtered, evaporated to a gum and purified by chromatography on silica, eluting with ether, to give the product, mp 68°-71°.
Reaction SMILES: C(#N)C.[C:4]([C:8]1[CH:13]=[CH:12][C:11](/[C:14](/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][CH3:27])[N:20]=2)=[CH:15]\C(O)=O)=[CH:10][CH:9]=1)([CH3:7])([CH3:6])[CH3:5].[Br:28]N1C(=O)CCC1=O>C(N(CC)CC)C>[Br:28]/[CH:15]=[C:14](/[C:19]1[N:20]=[C:21]([O:26][CH3:27])[C:22]([Cl:25])=[CH:23][CH:24]=1)\[C:11]1[CH:12]=[CH:13][C:8]([C:4]([CH3:7])([CH3:6])[CH3:5])=[CH:9][CH:10]=1
Reactant: COc1nc(/C(=C/C(=O)O)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1nc(/C(=C/Br)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25.4 %

Procedure:
A 97% acetonitrile solution (52 mL) containing triethylamine (26 μL) was added to (2E)-3-(4-tert-butylphenyl)-3-(5-chloro-6-methoxypyridin-2-yl)prop-2-enoic acid (1.3 g). N-bromosuccinimide (806 mg) was added thereto and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated under reduced pressure from the reaction solution. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to give the title compound as a colorless powder (363 mg, 25%).
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]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([Cl:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:30][C:21]1[CH:20]=[C:19]([CH:17]([NH:16][C:11](=[O:13])[CH2:10][N:7]2[C:6]3[C:14]([F:15])=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[CH3:18])[CH:24]=[CH:23][C:22]=1[C:25]([C:26]#[N:27])([CH3:29])[CH3:28]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(Cl)c1
Reactant: O=C(O)Cn1cnc2ccc(F)c(F)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Product: CC(NC(=O)Cn1cnc2ccc(F)c(F)c21)c1ccc(C(C)(C)C#N)c(Cl)c1
Yield: 53.3 %

Procedure:
To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (285 mg, 1.35 mmol) prepared according to scheme 2, 2-[4-(1-aminoethyl)-2-chlorophenyl]-2-methylpropanenitrile (300 mg 1.35 mmol) prepared according to scheme 17 and DMAP (325 mg, 2.69 mmol) stirred in anhydrous DMF (3.0 mL) is added HATU (511 mg, 1.35 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (300 mg, 55%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.83 (s, 6 H) 5.02 (q, J=7.03 Hz, 1H) 5.14 (s, 2H) 7.17 (ddd, J=11.33, 8.98, 7.42 Hz, 1H) 7.33 (dd, J=8.20, 1.95 Hz, 1H) 7.43 (ddd, J=8.89, 3.81, 1.37 Hz, 1H) 7.47 (d, J=2.34 Hz, 1H) 7.51 (d, J=8.20 Hz, 1H) 8.13 (s, 1H), MS [M+H], calcd: 379.1. found: 379.3.
Reaction SMILES: C(OC([N:8]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1)[CH2:9][C:10]([O:12][C@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[CH:25]=1)[CH2:14][C:15]1[C:20]([Cl:21])=[CH:19][N+:18]([O-:22])=[CH:17][C:16]=1[Cl:23])=[O:11])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[ClH:21].[Cl:21][C:20]1[CH:19]=[N+:18]([O-:22])[CH:17]=[C:16]([Cl:23])[C:15]=1[CH2:14][C@@H:13]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]([F:33])[F:32])=[C:26]([O:34][CH2:35][CH:36]2[CH2:37][CH2:38]2)[CH:25]=1)[O:12][C:10](=[O:11])[CH2:9][NH:8][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1
Reactant: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)C(=O)OC(C)(C)C)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(CNCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
To a solution of (S)-4-(2-(2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)-amino)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (258 mg, 0.355 mmol) in DCM (24 ml), HCl 4M in dioxane (1.2 ml, 4.80 mmol) was added drop wise, and the reaction was stirred at RT overnight. The volatiles were evaporated under vacuum and the residue was purified by trituration with diethylether affording (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(3,4-dimethoxybenzylamino) acetoxy)ethyl)pyridine 1-oxide hydrochloride as a beige solid (0.187 g, 0.282 mmol, 79% yield, MS/ESI+ 626.82 [MH]+, [αD]=−15.57, c=0.56, MeOH).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2].[CH:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CS(C)=O.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:25][CH2:24][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([Br:17])=[CH:11][CH:10]=3)[CH3:2]
Reactant: NCC1CCCCC1
Reactant: CCn1ncc2c(Cl)c3cc(Br)ccc3nc21
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(Br)ccc3nc21
Temperature: 110 °C
Yield: 98.4 %

Procedure:
A mixture of 1-ethyl-4-chloro-6-bromo-1H-pyrazolo[3,4-b]quinoline (6.5 g, 0.021 mol), cyclohexanemethylamine (5.46 g, 0.042 mol) and DMSO (20 ml) was heated at 110° C. overnight. The reaction mixture was cooled, poured into water and basified with NH4OH. The mixture was extracted with CH2Cl2 (2×100 ml) and the combined CH2Cl2 extracts were washed with brine, then evaporated to about 20 ml. The solution was purified by column chromatography on silica gel eluting with ethyl acetate to afford 8.0 g (98.8%) of 1-ethyl-6-bromo-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 158°-160° C.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[CH:15]([F:21])[CH:16]([F:20])[C:17]([OH:19])=[O:18].C([N-]C(C)C)(C)C.[Li+].[CH2:31](Br)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:22])[CH:15]([F:21])[C:16]([F:20])([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:17]([OH:19])=[O:18]
Reactant: BrCCc1ccccc1
Reactant: O=C(O)C(F)C(F)C(=O)c1ccc2oc3ccccc3c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc2oc3ccccc3c2c1)C(F)C(F)(CCc1ccccc1)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-dibenzofuran-2-yl-2,3-difluoro-4-oxo-butyric acid (1 equivalent, Example 6) in tetrahydrofuran cooled to -78° C. is added dropwise a solution of lithium diisopropylamide (2 equivalents). After stirring at -78° C. for 30 minutes, a solution of phenethyl bromide (1 equivalent) in tetrahydrofuran is added. The cooling bath is removed, and the reaction mixture gradually warms to room temperature and is stirred overnight. To this solution is added aqueous HCl (1 M) and ethyl acetate. The layers are separated, and the organic portion is washed with brine, dried (MgSO4), and concentrated in vacuo. The title compound is obtained by separation from the reaction by-product using silica gel chromatography (elution with chloroform/methanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[CH3:29][N:24]([CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:30])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[S:25]([CH3:28])(=[O:27])=[O:26]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN(C)S(C)(=O)=O)(c2ccccc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCN(C)S(C)(=O)=O)(c4ccccc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from N-(2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)ethyl)-N-methylmethanesulfonamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 459 Step 1. LC-MS Method 2 tR=0.989, m/z=508.1; 1H NMR (CDCl3) 1.53 (d, 3H), 2.17-2.32 (m, 5H), 2.63 (s, 3H), 2.71 (s, 3H), 2.81 (s, 3H), 2.93 (m, 2H), 3.22 (m, 1H), 5.67 (m, 1H), 7.08 (m, 2H), 7.21 (s, 2H), 7.25 (m, 3H), 7.33 (m, 2H), 7.61 (s, 1H), 7.71 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2]>CO.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][C:7]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)/C=C/C(C)(C)c1ccc(F)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)CCC(C)(C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (E)-4-(4-fluoro-phenyl)-4-methyl-pent-2-enoic acid ethyl ester (4.10 g) in methanol (150 ml) at room temperature was added platinum(IV) oxide (788 mg). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 2 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield a yellow oil, (3.97 g, 96%); MS (ISP): 239.2 ([M+H]+).
Reaction SMILES: [CH3:1][S@@:2]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[NH:4])=[O:3].[NH2:13][C:14]1[C:22]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([C:34]3[O:35][CH:36]=[CH:37][C:38]=3[CH3:39])=[O:33])[CH:26]=2)=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][N:15]=1>>[NH2:13][C:14]1[N:15]=[CH:16][C:17]([C:18]([N:4]=[S@:2]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([CH3:1])=[O:3])=[O:19])=[CH:21][C:22]=1[C:23]#[C:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([C:34]2[O:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[CH:26]=1
Reactant: COC(=O)CCCC[S@](C)(=N)=O
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)O)cnc2N)c1
Product: COC(=O)CCCC[S@@](C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1

Procedure:
In a manner similar to that described in Example 32, (R)-methyl 5-(S-methylsulfonimidoyl)pentanoate and 6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinic acid, were reacted to give the title compound.
Reaction SMILES: [ClH:1].C(OCC)(=O)C.C(O[C:13]([N:15](C)[C@H:16]([C:21]([NH:23][CH3:24])=[O:22])[C:17](=[O:20])[O:18][CH3:19])=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[CH3:24][NH:23][C:21](=[O:22])[C@H:16]([C:17](=[O:20])[O:18][CH3:19])[NH:15][CH3:13]
Reactant: CNC(=O)[C@H](C(=O)OC)N(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)[C@@H](NC)C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
A 4.0 mol/L-hydrochloric acid-ethyl acetate solution (0.13 L) was added to an ethyl acetate (0.19 L) solution of N2-(t-butoxycarbonyl)-N,N2,O-trimethyl-3-oxoserinamide (Intermediate 4-2, 62 g), and the mixture was stirred for 24 hours at room temperature. The precipitated solid was filtered off, and washed with ethyl acetate to obtain N,N2,O-trimethyl-3-oxoserinamide hydrochloride (Intermediate 5-2, white solid) (39 g, 84%).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[N:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[S:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[N:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[S:27][CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1nc(CCl)cs1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)n4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 4-(chloromethyl)-2-(trifluoromethyl)thiazole (172 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (141 mg).
Reaction SMILES: [N:1]1([C:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]C)=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[O:12])[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.B(Br)(Br)Br>>[N:1]1([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=2)=[O:12])[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: COc1ccc(C(=O)N2CCOc3cnccc32)cc1C(F)(F)F
Agent: BrB(Br)Br
Product: O=C(c1ccc(O)c(C(F)(F)F)c1)N1CCOc2cnccc21

Procedure:
By the same method as in the step b) of Example 12, (2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-(4-methoxy-3-trifluoromethyl-phenyl)-methanone (110 mg, 0.325 mmol) was reacted with 1M solution of boron tribromide (3.25 ml, 3.25 mmol) to obtain the target compound, (2,3-dihydro-pyrido[3,4-b][1,4]oxazin-1-yl)-(4-hydroxy-3-trifluoromethyl-phenyl)-methanone, as white solid (11 mg, 10%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:45]=[CH:46][C:47]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])=[CH:48][CH:49]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccc(C(F)(F)F)cc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 27.1 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0310 g, 0.0672 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 4-trifluoromethylbenzenesulfonyl chloride (0.0477 mL, 0.195 mmol) to obtain 4-(4-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0122 g, yield 27%).
Reaction SMILES: [CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](OC)=[O:13])=[CH:2][CH2:3][CH2:4][CH3:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][OH:13])=[CH:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC=Cc1ccccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCC=Cc1ccccc1CO

Procedure:
A solution of 9.70 g of methyl 2-(1-pentenyl)benzenecarboxylate, the product of Example 11b, was added to a mixture of 1.69 g lithium aluminum hydride and 300 ml of ethyl ether with stirring. After stirring for 0.5 hour, the reaction was quenched by successive additions of 1.7 ml of H2O, 1.7 ml of 15% NaOH, and 5.1 ml of H2O. The white solid was filtered and the filtrate was concentrated to obtain a yellow oil. Distillation gave the title compound, as a mixture of cis and trans isomers, bp 91°-102°/0.025 mm Hg.
Reaction SMILES: [C:1]([CH:5]1[CH2:13][CH2:12][C:11]2[N:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=3)[C:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:8][C:7]=2[CH2:6]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([OH:23])=[O:22])[CH:15]=1)[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCc2c(cc(-c3ccccc3)n2-c2ccc(O)c(C(=O)O)c2)C1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc2c(c1)cc(-c1ccccc1)n2-c1ccc(O)c(C(=O)O)c1

Procedure:
A mixture of 16 g. (0.041 mole) of 5-(t-butyl)-1-(3-carboxy-4-hydroxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole, 8 g. of 10% palladium on carbon, and 1.6 l. of xylene was heated under reflux under nitrogen for 23 hours and filtered. The filtrate was concentrated to 400 ml., cooled and filtered to provide 13.0 g. (82%) of crystals, m.p. 275°-276°. Recrystallization from acetonitrile gave crystals, m.p. 271°-273°.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5](Cl)=[S:6]>CCOCC>[CH3:3][N:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([NH:1][NH2:2])=[S:6]
Reactant: CN(C(=S)Cl)c1ccccc1
Reactant: NN
Solvent: CCOCC
Product: CN(C(=S)NN)c1ccccc1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a solution of 7.7 g (0.24 m) anhydrous hydrazine in 200 ml of dry ether, N-methyl-N-phenylthiocarbamyl chloride 20.4 g (0.11 m) was added below 5° C. with stirring. The mixture was stirred and allowed to warm to room temperature. The mixture was filtered and the residue resuspended in ~100 ml water and stirred. Filtration gave 8.8 g of the desired product as whitish powder, m.p. 121°-22°.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-])=O>CCOC(C)=O.O=[Pt]=O>[NH2:1][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Nc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-nitro-3-phenylaminobenzonitrile (560 mg, 2.34 mmol) in EtOAc (30 mL) was degassed with a stream of nitrogen, prior to addition of PtO2 (44 mg), and was stirred at RT under a hydrogen atmosphere for 2 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo affording 4-Amino-3-phenylaminobenzonitrile as a purple solid (500 mg, quantitative). LCMS: RT 3.20 min [M+H]+ 210.1.