Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:17])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(C)C>C1COCC1>[OH:15][CH2:14][C:11]1([CH3:17])[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Solvent: CSC
Solvent: C1CCOC1
Product: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A suspension of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (0.750 g, 3.08 mmol) in THF (5 mL) at rt under N2 was treated with 2M THF solution of BH3 SMe2 (1.541 mL, 3.08 mmol). After 18 h, the reaction was cooled in an ice bath and quenched by the addition of 5 mL of 1N NaOH. Partitioned between ether and water. Organic phase dried (MgSO4), filtered, and concentrated in vacuo to give 700 mg (99%) of tert-butyl 4-(hydroxymethyl)-4-methylpiperidine-1-carboxylate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 3.86-3.64 (m, 3H), 3.41 (s, 2H), 3.15 (ddd, J=13.6, 10.2, 3.5 Hz, 2H), 1.94-1.80 (m, 1H), 1.52-1.43 (m, 10H), 1.31 (dt, J=13.5, 3.8 Hz, 2H), 1.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]([C:11]([OH:13])=O)=[CH:8][C:7]([CH3:14])=[N:6][C:5]=2[S:4][C:3]=1[C:15](=[O:17])[NH2:16].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:14])=[CH:8][C:9]=2[C:11]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:13])[S:4][C:3]=1[C:15]([NH2:16])=[O:17]
Reactant: C1COCCN1
Reactant: Cc1cc(C(=O)O)c2c(N)c(C(N)=O)sc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C(=O)N2CCOCC2)c2c(N)c(C(N)=O)sc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-amino-2-carbamoyl-6-methyl-thieno[2,3-b]pyridine-4-carboxylic acid (see Example 10) (0.5 g, 2.0 mmol), morpholine (0.87 g, 10 mmol) and PyBop (0.88 g, 2.0 mmol) in DMF (10 mL) was stirred at room temperature overnight. It was diluted with water and extracted with methylene chloride (50 mL). Concentration of the organic phase the title compound as an orange solid (0.45 g, 70.3%).
Reaction SMILES: CC(O[C:5]([CH3:7])=[O:6])=O.[CH3:8][C@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[NH2:18].[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH3:8][C@H:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C@H:10]1[NH:18][C:5](=[O:6])[CH3:7]
Reactant: C[C@H]1Cc2ccccc2[C@H]1N
Reactant: CC(=O)OC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)N[C@@H]1c2ccccc2C[C@@H]1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of Ac2O (1.45 g, 14.2 mmole) in toluene (12 ml), was added dropwise a solution of (rac), (cis)-2-methyl-1-aminoindan (Ex. 39, 1.85 g, 12.6 mmole). The mixture was heated at 90° C. for 15 min, cooled to 70° C., and a solution of 1.1 g KOH in 8.3 ml water was added. The reaction mixture was stirred at ambient temperature for 2 hrs; the solid was collected by filtration, washed with toluene (10 ml), dried and crystallized from hexane:EtOAc, to give 1.85 g (9.8 mmole, 78%), mp: 146°-7° C.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:14].[O:15]=[CH:16][C:17]1[CH:25]=[CH:24][C:22]([OH:23])=[C:19]([O:20][CH3:21])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:23][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:14])[CH:16]=[O:15]
Reactant: Cc1nc(-c2ccccc2)sc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)ccc1OCc1sc(-c2ccccc2)nc1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 90.9 %

Procedure:
A mixture of 5-chloromethyl-4-methyl-2-phenyl-1,3-thiazole (2.30 g), vanillin (1.49 g), potassium carbonate (1.35 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-methoxy-4-[(4-methyl-2-phenyl-1,3-thiazol-5-yl)methoxy]benzaldehyde as pale-yellow crystals (3.02 g, yield 91%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 118-119° C.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]2[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][C:4]=12)[CH3:2].[CH2:17]([C:19]1[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([CH3:27])[C:20]=1[CH:28]=[CH:29][C:30]([OH:32])=[O:31])[CH3:18].Cl>[OH-].[Na+]>[CH2:17]([C:19]1[CH:24]=[C:23]([CH:25]=[CH:9][C:8]([C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]3[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][CH2:11][C:5]=23)=[O:10])[CH:22]=[C:21]([CH3:27])[C:20]=1[CH:28]=[CH:29][C:30]([OH:32])=[O:31])[CH3:18]
Reactant: CCc1sc(C(C)=O)c2c1CC(C)(C)CC2
Reactant: CCc1cc(C=O)cc(C)c1C=CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(C=CC(=O)c2sc(CC)c3c2CCC(C)(C)C3)cc(C)c1C=CC(=O)O
Yield: 60.1 %

Procedure:
A solution of 1-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-ethanone (200 mg, 0.846 mmol) and 3-(2-ethyl-4-formyl-6-methyl-phenyl)-acrylic acid (203 mg, 0.931 mmol) in methanolic NaOH (8 mL, 10 g NaOH in 100 mL methanol) is stirred at rt for 3 h before it is carefully acidified to pH 1 by adding 2 N aq. HCl. The mixture is extracted twice with DCM and the organic extracts are washed with water and brine, dried over MgSO4, filtered and evaporated. The crude product is crystallised from acetonitrile (40 mL) to give 3-{2-ethyl-4-[3-(3-ethyl-5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-3-oxo-propenyl]-6-methyl-phenyl}-acrylic acid (222 mg) as yellow crystals. From the mother liquor a second crop (29 mg) of product can be obtained after purification by prep. HPLC (Grom-Sil 120 ODS-4-HE, 30×75 mm, 10 μm, acetonitrile/water (0.5% HCOOH), 20% to 95% acetonitrile); LC-MS: tR=1.20 min, [M+1]=437.31.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25]CC1C=CC=CC=1)(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd]>[C:1]([O:5][C:6](=[O:33])[CH2:7][C@H:8]([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])(=[O:18])=[O:17])[C:9]([N:11]([O:13][CH3:14])[CH3:12])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: CON(C)C(=O)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccccc1O
Yield: 104.8 %

Procedure:
(S)-3-(2-Benzyloxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester (3.54 g) in TBF(50 mL) was treated with 20% Pd/C (0.30 g) at 50 psi hydrogen until uptake was complete. The reaction was filtered and the filtrate was evaporated to give (S)-3-(2-hydroxy-benzenesulfonylamino)-N-methoxy-N-methyl-succinamic acid tert-butyl ester as a colorless oil (3.01 g, 100%). 1H NMR (CDCl3) 8.82(s,1H), 7.63(d,1H), 7.44(t,1H), 6.98(m,2H), 5.95(d,1H), 4.62(bs,1H), 3.62(s,3H), 3.03(s,3H), 2.65-2.40(AB quartet, 2H), 1.43(s,9H).
Reaction SMILES: [CH2:1]([P:3]([O-:9])[O:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12]>C1(C)C=CC=CC=1>[CH2:1]([P:3]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])([CH2:12][CH2:11][C:10]([OH:14])=[O:13])=[O:9])[CH3:2]
Reactant: CCCCOP([O-])CC
Reactant: C=CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCOP(=O)(CC)CCC(=O)O
Yield: 90.5 %

Procedure:
149 g (1 mol) of butyl ethylphosphonite (produced as in Example 2) and 86 g (1.2 mol) of acrylic acid in 217 g of toluene are heated to about 100° C. While stirring, 124 g of a 10% strength solution of WakoV65 in toluene are metered in. The solvent is distilled off in vacuo to leave 201 g (91% of theory) of 3-(ethylbutoxyphosphinyl)propionic acid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[NH:13][C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23].N1C2C(=CC=CC=2)[C:26]2([C:36]3=CC4OCOC=4[CH:43]=[C:35]3[O:34][CH2:33]2)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1>>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]3[O:22][CH2:21][C:11]4([C:19]5[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=5)[N:13]([CH2:43][C@H:35]5[CH2:36][CH2:26][CH2:33][O:34]5)[C:12]4=[O:20])[C:9]3=[CH:10][C:5]=2[O:4][C:3]1=[O:23]
Reactant: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: Cn1c(=O)oc2cc3c(cc21)OCC31C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indole]-2,2′(1′H,3H)-dione to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methyl benzenesulfonate, 3-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-2H-spiro[benzofuro[6,5-d]oxazole-7,3′-indoline]-2,2′(3H,6H)-dione was obtained (69%) as a colorless solid: mp 186-187° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.36-7.29 (m, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.06-7.02 (m, 2H), 6.63 (d, J=6.9 Hz, 1H), 4.85-4.73 (m, 2H), 4.24-4.16 (m, 1H), 3.81-3.59 (m, 4H), 3.31 (s, 3H), 2.00-1.75 (m, 3H), 1.69-1.55 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ177.2, 157.3, 154.9, 143.4, 136.6, 133.3, 131.9, 129.3, 123.9, 123.3, 122.3, 110.2, 105.0, 92.9, 80.0, 76.1, 67.7, 57.7, 44.3, 29.1, 28.6, 25.5; MS (ES+) m/z 392.7 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][C:19]([NH2:26])([C:21]1[N:25]=[CH:24][O:23][N:22]=1)[CH3:20]>>[CH3:18][C:19]([NH:26][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])([C:21]1[N:25]=[CH:24][O:23][N:22]=1)[CH3:20]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1ncon1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ncon1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and 1-methyl-1-[1,2,4]oxadiazol-3-yl-ethylamine (CAN 1153757-41-5) as starting materials, MS (LC/MS): 343.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.P(=O)(O)(O)O>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([C@@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@H]1O[C@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H](S)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
A mixture of (2S,3R)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (30 mg), methyl 3-mercaptopropionate (0.09 ml) and 28% sodium methoxide-methanol (0.08 ml) in methanol (2 ml) was refluxed for 2 hours, after which 28% sodium methoxide-methanol (0.04 ml) was added and the mixture was refluxed for another hour. Then, methyl 3-mercaptopropionate (0.04 ml) was added and the mixture was further refluxed for 2 hours. The reaction mixture was cooled, diluted with water (2 ml), neutralized with 5% aqueous phosphoric acid solution and extracted with methylene chloride (3 ml×2). The extract was dried over anhydrus sodium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (1×5 cm) using ethyl acetate-hexane (3:1) as the eluent. The desired fraction was concentrated and the residue was crystallized from ethyl acetate-isopropyl ether to give (2S,3S)-2-(2,4-difluorophenyl)-3-mercapto- 1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 42:11 mg) as colorless prisms.
Reaction SMILES: [C:1]1([NH:7][C:8]([C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[C:28]([NH2:33])[N:27]=1>CC#N>[NH2:33][C:28]1[N:29]=[C:30]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:10]([C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:11]2)[CH:31]=[C:26]([Cl:25])[N:27]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCC[C@@H](C(=O)Nc3ccccc3)C2)n1
Temperature: 160 °C
Yield: 43.4 %

Procedure:
To a solution of (3R)—N-phenyl-3-piperidinecarboxamide (339 mg, 1.66 mmol) in CH3CN (3 mL) in a 5 mL microwave vial, was added Hunig's base (0.87 mL, 4.98 mmol) and 4,6-dichloro-2-pyrimidinamine (299 mg, 1.83 mmol), and the reaction mixture was heated at 160° C. under microwave conditions for 0.5 hours. A solid formed upon cooling of the reaction mixture. The solid was then isolated by filtration, washing with CH3CN to afford the crude title compound (239 mg) as a light brown solid. LC-MS (ES) m/z=332 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18].CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])=[O:5]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1ccccc1O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution of 2-chloronicotinoyl chloride (2.91 g, 16.6 mmol) in ethyl acetate (50 mL) was added to a mixture of 2-aminophenol (2.00 g, 18.3 mmol) and DIPEA (4.8 mL, 27.5 mmol) in ethyl acetate (50 mL) at 4° C. The reaction mixture was stirred for 1 hour. The organic mixture was washed with water and brine then concentrated under reduced pressure. The residue was dissolved in ethanol/THF 1:1 (75 mL) and 15% sodium hydroxide (25 mL) and the mixture was stirred at 50° C. for 45 min. The mixture was cooled down to room temperature and concentrated in vacuo to one third volume and then acidified to pH=2 with 3M HCl. The solid was filtered, washed with water and dried to afford title compound 13 (3.69 g, 81%) as a beige solid. LRMS (ESI): (calc) 248.04. (found) 249.2 (MH)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH:12]=O)[O:3]1.[NH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1>CC(O)=O.C(Cl)Cl>[CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[CH:21][CH:20]=2)[O:3]1
Reactant: CC1(C)OB(c2cccc(C=O)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(NCc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (100 mg, 0.43 mmol), tert-butyl 4-aminobenzoate (83 mg, 0.43 mmol), NaHB(OAc)3 (273 g, 1.29 mmol) and AcOH (2 drops) in 30 mL of DCM was stirred at room temperature overnight. The mixture was washed with sat NaHCO3 (30 mL), water (2×30 mL), and brine (30 mL) dried over Na2SO4 concentrated under reduce pressure to give a crude tert-butyl 4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylamino)benzoate (130 mg) as a black oil. LC-MS: 410 [M+H]+, tR=1.92 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[CH3:13]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][CH3:13])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: OCc1cc(F)cc(F)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc(F)cc(F)c1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of (3,5-difluorophenyl)methanol (1.98 g, 13.7 mmol) in THF (20 mL) at 0° C. was added sodium hydride (1.0 g, 25 mmol) in portions. The mixture was stirred at 0-5° C. for 1 h, and then methyl iodide (4.3 mL, 69 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic extracts were concentrated and the resulting residue was columned on 40 g silica gel, eluting with 0-40% EtOAc in hexanes, to give a colorless oil (2.1 g, 97%). 1H NMR (300 MHz, CDCl3) δ 6.86 (m, 2H), 6.71 (m, 1H), 4.43 (s, 2H), 3.38 (s, 3H) ppm.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[CH2:22][CH3:23].C[O:25][B:26](OC)[O:27]C.Cl>O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[C:12]([CH2:13][CH3:14])[C:7]([B:26]([OH:27])[OH:25])=[C:8]([CH2:22][CH3:23])[CH:9]=2)=[CH:16][CH:17]=1
Reactant: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(Cl)cc2)cc(CC)c1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
tert-Butyllithium (1.6 M solution in hexane, 13 ml, 0.02 mol) is added dropwise to a solution of 4-bromo-4′-chloro-3,5-diethylbiphenyl (4.5 g, 0.0139 mol) in dry tetrahydrofuran (50 ml) at −78° C. under an atmosphere of nitrogen. The reaction mixture is stirred at −78° C. for 30 minutes, then trimethylborate (9.3 ml, 0.083 mol) is added. The resulting mixture is stirred at −78° C. for 1 hour and then allowed to warm to room temperature over 3 hours. The reaction mixture is acidified with 0.1 N aqueous hydrochloric acid solution and the mixture is stirred at room temperature overnight. The mixture is extracted with ethyl acetate (3×100 ml). The organic layers are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated. The residue is purified by column chromatography on silica gel to give 4′-chloro-3,5-diethylbiphen-4-ylboronic acid as a white powder (1.8 g).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>ClC(Cl)C.C1(C)C=CC=CC=1>[S:28]1[CH2:2][CH2:3][N:4]=[C:5]1[C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:16]([O-:18])=[O:17]
Reactant: O=C(NCCCl)c1cc2cccc([N+](=O)[O-])c2[nH]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc2cc(C3=NCCS3)[nH]c12
Yield: 60 %

Procedure:
7-Nitro-1H-indole-2-carboxylic acid (2-chloro-ethyl)-amide (267 mg, 1 mmol) prepared in Step B was dissolved in dichloroethane (10 mL) and toluene (10 mL), and Lawesson's Reagent (1.29 g, 3.2 mmol) was added thereto. The mixture was refluxed for 4 h, and distilled under reduced pressure. Water was added thereto, and the reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and the concentrate was purified by column chromatography to give the title compound as a product of the cyclization reaction (148 mg, Yield 60%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:26])[C:13]2[C:18]([Cl:19])=[C:17]([Cl:20])[C:16]([Cl:21])=[C:15]([Cl:22])[C:14]=2[C:23]([OH:25])=O)=[C:4]1[CH3:27])[CH3:2].[CH2:28]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]3=2)[CH:32]=[C:31]1[CH3:43])[CH3:29]>C(OC(=O)C)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2([C:32]3[C:33]4[C:38](=[C:37]5[CH:39]=[CH:40][CH:41]=[CH:42][C:36]5=[CH:35][CH:34]=4)[N:30]([CH2:28][CH3:29])[C:31]=3[CH3:43])[C:13]3[C:14](=[C:15]([Cl:22])[C:16]([Cl:21])=[C:17]([Cl:20])[C:18]=3[Cl:19])[C:23](=[O:25])[O:26]2)=[C:4]1[CH3:27])[CH3:2]
Reactant: CCn1c(C)cc2ccc3ccccc3c21
Reactant: CCn1c(C)c(C(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCn1c(C)c(C2(c3c(C)n(CC)c4c3ccc3ccccc34)OC(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c32)c2ccccc21
Yield: 31.1 %

Procedure:
A solution of about 4.5 grams of 1-ethyl-2-methyl-3-(2-carboxy-3,4,5,6-tetrachlorobenzoyl)indole and about 3.2 grams of 1-ethyl-2-methyl-1H-benz[g]indole in 50 milliliters of acetic anhydride is heated at 90° C. for about four hours. The product is isolated as disclosed previously. 2.0 grams of the title compound is obtained having a melting point of 170°-177° C. A solution of the product imparts a purple color to paper coated with a phenolic resin or silton clay or a combination of the two. The calculated analysis for C34H26N2Cl4O2, the title compound, is C, 64.17%; H, 4.12%; N, 4.40%; and Cl, 22.28%. Found, on analysis: C, 64.33%; H, 4.19%; N, 4.49%; Cl, 22.37%.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][NH:24][CH:25]([CH3:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC(C)N
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)CC(C)NCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (30 mg, 0.097 mmol), ethyl 3-aminobutanoate (CAS no. 5303-65-1) (19 mg, 0.145 mmol), and acetic acid (17 mg, 0.291 mmol) were dissolved in dichloroethane (2 mL). The mixture was stirred at r.t. for 10 min under nitrogen atmosphere. Then NaBH(OAc)3 (41 mg, 0.194 mmol) was added to the mixture and the mixture was stirred at r.t. for 15 h. Then saturated NaHCO3 was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using dichloromethane:methanol 10:1 to give produce ethyl 3-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methylamino)butanoate (40 mg, 88%) as a slight yellow solid. ESI-MS: 426.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.70-7.65 (m, 3H), 7.41 (d, 1H), 7.13-7.09 (m, 2H), 4.28-4.23 (m, 1H), 4.12 (q, 2H), 3.98-3.88 (m, 2H), 3.22-3.18 (m, 1H), 2.53-2.42 (m, 2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m, 2H), 1.26-1.09 (m, 9H), 0.90 (s, 9H).
Reaction SMILES: Cl.O1CCOCC1.C(OC(=O)[NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([N:27]1[CH2:41][C:30]2=[C:31]3[N:36]([N:37]=[C:29]2[CH2:28]1)[C:35]([CH3:38])=[C:34]([Cl:39])[C:33]([CH3:40])=[N:32]3)=[O:26])(C)(C)C>C(Cl)Cl>[ClH:39].[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([N:27]1[CH2:41][C:30]2=[C:31]3[N:36]([N:37]=[C:29]2[CH2:28]1)[C:35]([CH3:38])=[C:34]([Cl:39])[C:33]([CH3:40])=[N:32]3)=[O:26]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCCNC(=O)OC(C)(C)C)C3
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OCCN)C3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 181.7 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (1.67 mL; 6.7 mmol; 15 eq.) was added to a solution of Example 174 (225 mg; 0.45 mmol; 1 eq.) in DCM (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes then concentrated in vacuo to afford the title compound (180 mg, 92%) as a yellow solid. 1H NMR (DMSO-d6) δ 7.92 (br s, 3H), 7.44 (ddd, J=8.4, 6.8, 4.3 Hz, 1H), 7.18 (dd, J=11.3, 2.4 Hz, 1H), 6.95 (td, J=8.4, 2.3 Hz, 1H), 4.85 (d, J=8.6 Hz, 2H), 4.59 (d, J=14.9 Hz, 2H), 4.32-4.26 (m, 2H), 3.15 (t, J=5.0 Hz, 2H), 2.86 (s, 1.6H), 2.82 (s, 1.4H), 2.62 (s, 1.4H), 2.56 (s, 1.6H). HPLC (max plot) 99.4%, Rt 2.69 min. UPLC/MS: (MS+) 404.3 ([M+H]+).