Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C([Li])(C)(C)C.[CH2:12]([C@@H:14]1[O:16][CH2:15]1)[Cl:13]>CCOCC>[Cl:13][CH2:12][C@H:14]([OH:16])[CH2:15][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClC[C@H]1CO1
Reactant: Brc1cccs1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: O[C@@H](CCl)Cc1cccs1
Reaction time: 1.5 h
Yield: 25.8 %

Procedure:
To a solution of 2-bromothiophene (0.95 mL, 9 mmol) in ether (60 mL) cooled to −100° C. was added t-butyl lithium (5.41 mL of 1.7 M in pentane, 9 mmol) by dropwise addition. The reaction mixture was stirred at this temperature for 30 min. (R)-Epichlorohydrin (1.08 mL, 14 mmol) was added and the −100° C. bath was replaced with an ice/ethanol bath. The reaction was stirred at this temperature for 1.5 h and then stirred in an ice-bath for an additional 1.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3 times). The combined organic phases were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (50% EtOAc in heptane eluent) to afford (R)-1-chloro-3-thiophen-2-yl-propan-2-ol (410 mg, 25%) as a brown oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.28 (d, J=4.14 Hz, 1H) 3.06-3.21 (m, 2H) 3.46-3.73 (m, 2H) 4.08 (d, J=5.65 Hz, 1H) 6.91 (dd, J=3.39, 0.94 Hz, 1H) 6.98 (dd, J=5.09, 3.39 Hz, 1H) 7.21 (dd, J=5.18, 1.22 Hz, 1H).
Reaction SMILES: CO[C:3]1[C:11](OC)=[CH:10][C:9]2[C:5](=[CH:6][O:7][C:8]=2[C:14]2[CH:22]=[CH:21][C:17]3[O:18][CH2:19][O:20][C:16]=3[CH:15]=2)[CH:4]=1.[C:23]([C:30]([O:32][CH2:33]C)=[O:31])#[C:24][C:25]([O:27][CH2:28]C)=[O:26]>C(O)(=O)C>[O:18]1[C:17]2[CH:21]=[CH:22][C:14]([C:8]3[C:9]4[C:5](=[CH:4][CH:3]=[CH:11][CH:10]=4)[C:6]([OH:7])=[C:23]([C:30]([O:32][CH3:33])=[O:31])[C:24]=3[C:25]([O:27][CH3:28])=[O:26])=[CH:15][C:16]=2[O:20][CH2:19]1
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: COc1cc2coc(-c3ccc4c(c3)OCO4)c2cc1OC
Solvent: CC(=O)O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc3c(c2)OCO3)c2ccccc2c1O

Procedure:
In certain embodiments, the Diels-Alder reaction of 5-(5,6-dimethoxyisobenzofuran-1-yl)benzo[d][1,3]dioxole and diethyl acetylene-dicarboxylate in the presence of acetic acid and at 140° C. provides dimethyl 1-(benzo[d][1,3]dioxol-5-yl)-4-hydroxynaphthalene-2,3-dicarboxylate.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([CH3:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:23]([NH:25]O)=[NH:24])[CH3:19]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:10]3[O:12][N:25]=[C:23]([C:22]4[CH:27]=[C:28]([CH3:35])[C:29]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:20]([CH2:18][CH3:19])[CH:21]=4)[N:24]=3)[CH:13]=[C:14]([O:16][CH3:17])[N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1cc(C(=N)NO)cc(C)c1NS(C)(=O)=O
Reactant: COc1cc(C(=O)O)cc(C2CCCCC2)n1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCCC4)c3)n2)cc(C)c1NS(C)(=O)=O
Yield: 10.1 %

Procedure:
The title compound (7 mg) is prepared in analogy to Example 11 starting from 2-cyclohexyl-6-methoxy-isonicotinic acid (40 mg, 147 μmol) and 3-ethyl-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine (42 mg, 155 mmol); LC-MS**: tR=0.94 min, [M+H]+=471.02; 1H NMR (CDCl3): δ1.35 (t, J=7.8 Hz, 3H), 1.40-1.70 (m, 5H), 1.77-1.84 (m, 1H), 1.88-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.56 (s, 3H), 2.71-2.81 (m, 1H), 2.93 (q, J=7.0 Hz, 2H), 3.18 (s, 3H), 4.03 (s, 3H), 5.87 (s, 1H), 7.32 (s, 1H), 7.49 (s, 1H), 7.97 (s, 1H), 7.99 (s, 1H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:41][CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Product: COc1cc(C(=O)NC2CCN(C)CC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and 1-methylpiperidin-4-amine as described in the general procedure for amide bond synthesis. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60-1.73 (m, 11H), 1.88-2.21 (m, 8H) 2.78 (br. s., 2H) 3.73 (br. s., 1H) 3.91 (s, 3H) 4.08 (t, J=13.8 Hz, 2H) 4.81 (d, J=8.1 Hz, 1H) 7.18 (d, J=6.6 Hz, 1H) 7.91 (br. s., 1H) 8.04 (s, 1H) 8.24 (d, J=13.4 Hz, 1H) 8.30 (s, 1H). [M+H] calc'd for C27H34F3N7O3, 562. found 562.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15]>CCOC(C)=O.[Pd].C(N(CC)CC)C>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:10]#[C:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:19][CH:20]=1)=[O:15]
Reactant: COC(=O)c1ccc(Br)s1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 63406.2 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (from Preparation 41, 1.67 mmol, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylpyosphine(O) palladium (0.622 g, 0.0538 mmol), Cul (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetronitrile was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound of Step A as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:3]=1.[Cl-].[NH4+]>C(O)C.[Fe]>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[N:4]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)nn(CCN3CCCC3)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1ccc2c(Cl)nn(CCN3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
A mixture of 3-chloro-6-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (2.3 g, 7.8 mmol), iron powder (3.5 g, 62 mmol), and ammonium chloride (0.21 g, 3.9 mmol) in 80% Ethanol was heated to reflux for 3 hours, cooled to room temperature, and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 20 mL) for 15 minutes, filtered through a plug of silica gel, which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (1.7 g, 80%). 1H NMR (300 MHz, DMSO-d6) ppm 1.64 (m, 4H), 2.45 (m, 4H), 2.78 (t, J=6.44, 2H), 4.21 (t, J=6.44, 2H), 5.56 (s, 2H), 6.48 (m, 1H), 6.58 (m, 1H), 7.25 (m, 1H); MS (DCI/NH3) m/z 265 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:22])[CH:20]=[CH2:21].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C.N#N>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C:17]2[N:16]=[CH:15][C:14](/[CH:21]=[CH:20]/[C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(Br)cnc21
Reactant: C=CC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CC(C)(C)OC(=O)N1CCCc2cc(/C=C/C(=O)OCc3ccccc3)cnc21
Temperature: 25 °C
Yield: 53.8 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)-6-bromo-1,2,3,4-tetrahydro-1,8-naphthyridine (1.79 g, 5.70 mmole), benzyl acrylate (1.11 g, 6.84 mmole), Pd(OAc)2 (65 mg, 0.29 mmole), P(o-tolyl)3 (173 mg, 0.57 mmole), and (i-Pr)2NEt (2.5 mL, 14.25 mmole) in propionitrile (30 mL) was degassed (3×N2/vacuum) then heated to reflux. After 18 hr the mixture was cooled to RT and concentrated. Flash chromatography on silica gel (25% EtOAc/hexanes) gave the title compound (1.21 g, 54%) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.53 (s, 1H), 7.40 (m, 5H), 6.43 (d, J=16.0 Hz, 1H), 5.25 (s, 2H), 3.77 (m, 2H), 2.75 (t, J=6.5 Hz, 2H), 1.93 (m, 2H), 1.54 (s, 9H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([F:29])=[C:10]([F:28])[C:11]3[C:21](=[O:22])[C:20]([C:23]([O:25]CC)=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)[CH:5]=[C:4]([CH3:30])[N:3]=1.C([O-])(=O)C.[Na+]>Cl>[CH3:30][C:4]1[CH:5]=[C:6]([C:8]2[C:9]([F:29])=[C:10]([F:28])[C:11]3[C:21](=[O:22])[C:20]([C:23]([OH:25])=[O:24])=[CH:19][N:13]4[C@@H:14]([CH3:18])[CH2:15][O:16][C:17]=2[C:12]=34)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1cn2c3c(c(-c4cc(C)nc(C)c4)c(F)c(F)c3c1=O)OC[C@@H]2C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Cc1cc(-c2c(F)c(F)c3c(=O)c(C(=O)O)cn4c3c2OC[C@@H]4C)cc(C)n1
Yield: 51.8 %

Procedure:
A solution of 1.20 g ethyl (S)-10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate in 15 ml 1M hydrochloric acid was heated at reflux for 2 hours. The reaction mixture was cooled, poured into sodium acetate solution and extracted with methylene dichloride. The extract was dried (sodium sulfate) and concentrated, and the residue was crystallized from methanol to give 0.58 g (S)-10-(2,6-dimethyl-4-pyridinyl)-8,9-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid as a colorless solid, m.p. 307°-310° C., [α]D25 =-39.1° (1% in chloroform).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)=[CH:32][CH:31]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(4-chloro-phenyl)-4-methyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.14 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/heptane) to yield the title compound as an off-white solid (0.087 g, 20%). MS (ISP) 442.4 [(M+H)+]; mp 227° C.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C@@H:23]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:24][CH:25]([CH3:26])[CH3:27]
Reactant: CC(C)C[C@@H](/C=C/CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@@H](/C=C/CCO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a solution of the TBDPS-protected alcohol 8b (584 mg, 1.10 mmol, crude) in dry THF (9 mL) at 0° C. was added TBAF (1.0M/THF, 1.38 mL, 1.38 mmol), and the reaction mixture was allowed to warm to rt while stirring under argon for 3.5 h, then quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 194 mg (60%, 2 steps) of the title compound as a colorless oil. [α]D23-6.4 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 7.20-7.40 (m, 5 H), 5.65-5.49 (m, 1 H), 5.44 (dd, 1 H, J=15.3, 6.6 Hz), 5.09 (s, 2 H), 4.67 (bs, 1 H), 4.16 (m, 1 H), 3.63 (bs, 2 H), 2.28 (q, 2 H, J=6.0 Hz), 1.82 (bs, 1 H), 1.65 (m, 1 H), 1.40-1.25 (m, 2 H), 0.80-1.00 (m, 6 H); HRMS (E81) m/z calcd for C17H23NO3Na 314.1732. found 314.1739.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH3:21])[CH2:9]2)=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=[C:27]([Br:29])[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].O1CCOCC1>[Br:29][C:27]1[CH:28]=[C:23]([NH:1][C:2]2[N:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:10]([CH3:21])[CH2:9]3)=[CH:4][CH:3]=2)[C:24](=[O:31])[N:25]([CH3:30])[CH:26]=1
Reactant: C[C@@H]1CN(c2ccc(N)nc2)CCN1C(=O)OC(C)(C)C
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (15 mL), 108b (800 mg, 2.7 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (720 mg, 2.7 mmol), and cesium carbonate (1.76 g, 5.4 mmol). After bubbling nitrogen through the suspension for 3 minutes, Xantphos (78 mg, 0.14 mmol) and tris(dibenzylideneacetone)dipalladium(0) (128 mg, 0.14 mmol) were added. The system was subject to three cycles of vacuum/argon flash and heated at reflux for 3 h. It was then cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous layer was separated and extracted with ethyl acetate (50 mL×2). The combined organic layer was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column chromatography eluting with 10:1 dichloromethane/methanol to afford 108c as a yellow solid (624 mg, 47%). LCMS: [M+H]+ 480
Reaction SMILES: [Na+].[C:2]1([CH3:11])[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([C:16](=[CH2:19])[CH:17]=[O:18])[CH2:13][CH2:14][CH3:15]>C(O)(=O)C.O>[CH3:11][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:19][CH:16]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:17]=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: C=C(C=O)CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(C=O)CS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a stirred solution of 4-toluenesulfinate sodium salt (10.10 g, 56.68 mmol) in 35 mL of acetic acid at 50° C., is added 2-butylacrolein (10.6 mL, 79.66 mmol) slowly. The reaction mixture is kept at 50° C. for 3 hours. After cooling to room temperature, the mixture is diluted with 50 mL of water and extracted with ethyl acetate (2×25 mL). The combined extract is washed with saturated NaHCO3, water, brine, and dried with MgSO4. After removing solvents, the product is obtained as a yellow liquid in 75% yield.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([C:16]([N:18]2[CH2:23][CH:22]=[C:21]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[CH2:20][CH2:19]2)=O)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1>[CH:7]1([CH2:16][N:18]2[CH2:19][CH:20]=[C:21]([C:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][CH:25]=3)[CH2:22][CH2:23]2)[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1
Reactant: O=C(C1CCc2ccccc21)N1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C1=C(c2c[nH]c3ccccc23)CCN(CC2CCc3ccccc32)C1
Temperature: 25 °C

Procedure:
To a solution of LiAlH4 (1.6 g) in dry THF (100 ml) kept at 0° C. was added drop-wise a solution of 3-[1-(1-indanylcarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole 4a (4.7 g) in dry THF (200 ml). The mixture was left stirring over-night at room temperature. Excess LiAlH4 was destroyed by cautiously adding 10% water in THF. The precipitated inorganic salts were filtered off. The solvents were evaporated leaving crude title compound (5.2 g). Recrystallization from 2-propanol afforded 2.8 g of pure 5a. Mp 168-170° C. 1H NMR (CDCl3): δ 1.85-2.00 (m, 1H); 2.30-2.45 (m, 1H); 2.60 (dd, 1H); 2.60-2.70 (m, 2H); 2.70-3.00 (m, 5H); 3.30 (broad t, 2H); 3.45 (quin, 1H); 6.25 (broad t, 1H); 7.10-7.25 (m, 6H); 7.30-7.40 (m, 2H); 7.90 (d, 1H); 8.10 (broad s, 1H). MS m/z (%): 329 (MH+, 2%), 160 (10%), 131 (100%), 91 (19%).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].CC([N:21](C)C)=O.BrC(C)(C)C(N)=O.[OH-].[Na+]>O>[NH2:21][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)N(C)C
Reactant: CC(=O)c1ccc(N2CCN(C)CC2)cc1O
Agent: CC(C)(Br)C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C)CC2)cc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a solution of 1-[2-hydroxy-4-(4-methyl-piperazin-1-yl)-phenyl]-ethanone (5.22 g, 22.2 mmol) in DMA (50 mL) NaOH (2.67 g, 66.6 mmol) was added. The mixture was stirred at room temperature for 1 h, after which time 11.1 g (66.7 mmol) of 2-bromo-2-methylpropanamide was added and the mixture was stirred at room temperature overnight. 8.01 g (200 mmol) of NaOH was added and the resulting mixture was stirred at 100° C. for 2 h, then 50 mL of water was added and the mixture was stirred at 100° C. for 1 h. After cooling to room temperature, the mixture was concentrated and then diluted with DCM and washed with water, dried over sodium sulfate and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 95/5) to afford 1.51 g of the title compound (30% yield).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[N:16]=[N:17][NH:18][CH:19]=3)=[C:9]([O:20]C)[C:8]2=[S:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[N:16]=[N:17][NH:18][CH:19]=3)=[C:9]([OH:20])[C:8]2=[S:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=S
Yield: 93.1 %

Procedure:
Reaction of 160 (0.062 g, 0.198 mmol) and 1M BBr3 in CH2Cl2 (0.218 mmol) within 48 h as described for synthesis of 148a gave compound 161 (0.055 g, 93%) as a dark violet solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.73 (d, J=7.3 Hz, 2H), 7.51 (s, 1H), 7.40 (t, J=7.5 Hz, 2H), 7.33 (t, J=7.3 Hz, 1H), 6.95 (dd, J=9.2, 7.2 Hz, 2H), 6.46 (m, 1H), 5.08 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 168.47, 155.10, 147.75, 132.00, 129.82, 128.77, 128.30, 125.53, 120.90, 113.66, 112.61, 57.45, 46.41. HRMS (EI) calcd for C15H14N4OS [M]+ 298.088. found 298.0888.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:21]1([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:27]([N:28]1[CH2:33][CH2:32][N:31]([CH2:19][CH2:18][CH2:17][CH2:16][CH:14]2[O:13][N:12]=[C:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:15]2)[CH2:30][CH2:29]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C2=NOC(CCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)C2)cc1OC
Yield: 68.8 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (31.0 mg, 0.111 mmol), 1-(diphenylmethyl)piperazine (25.6 mg, 0.101 mmol), molecular sieve (5 beads) and NaBH(OAc)3 (64.6 mg, 0.308 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 35.7 mg (68.4%) of the target compound was obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)C(C)C)C.[C:20]([C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][C:42](O)=[O:43])=[CH:37][C:36]=3[Cl:45])=[CH:31][CH:30]=2)[C:26]([CH3:46])=[N:25][C:24]=1[CH3:47])(=[O:22])[NH2:21].Cl.CN(C)CCCN=C=NCC.N1(O)C2C=CC=CC=2N=N1>CN(C=O)C>[C:20]([C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:2][C@@H:3]([CH:8]([CH3:10])[CH3:9])[C:4]([O:6][CH3:7])=[O:5])=[O:43])=[CH:37][C:36]=3[Cl:45])=[CH:31][CH:30]=2)[C:26]([CH3:46])=[N:25][C:24]=1[CH3:47])(=[O:22])[NH2:21]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)O)cc3Cl)cc2)nc1C(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 123.5 %

Procedure:
A mixture of (S)-methyl 2-amino-3-methylbutanoate hydrochloride (95 mg, 0.57 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (342 μL) were treated with a solution of 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetic acid (Example 1; 205 mg, 0.52 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (70.0 mg, 0.52 mmol) and N-ethyl-N-isopropylpropan-2-amine (99 μL, 0.57 mmol) in DMF (2049 μL) at RT. The resulting solution was stirred at RT for 20 hours. The reaction mixture was evaporated to dryness and redissolved in DCM (5 mL), and washed with water (5 mL). The organic layer was evaporated to afford (S)-methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-3-methylbutanoate (327 mg, 124%) which was used without further purification.