Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combined phenylacetonitrile (5.85 g, 50.0 mmol) and THF (30 mL). Cooled in a dry-ice/acetone bath. Added dropwise, sodium bis-(trimethylsilyl)amide (100 mL, 1.0M in THF, 100 mmol, 2 eq.). After the addition was complete, allowed to warm to ambient temperature. Cooled in a dry-ice/acetone bath. Added dropwise, ethyl bromoacetate (11 mL, 99 mmol). After the addition was complete, warmed to ambient temperature and stir for 3 h. Partitioned the reaction mixture between diethyl ether (200 mL) and water (200 mL). The organic layer was extracted with H2O (3×150 mL), 1N HCl (2×100 mL), 5% NaHCO3 (2×100 mL), and brine (1×150 mL). Dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. Chromatographed on silica gel eluting with 20% ethyl acetate in hexane to obtain the title compound:
Reaction SMILES: [CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].S(Cl)([Cl:28])=O>C1(C)C=CC=CC=1>[CH2:1]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([C:23]([Cl:28])=[O:25])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCOc1ccc([C@H]2CC[C@H](C(=O)O)CC2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCCOc1ccc([C@H]2CC[C@H](C(=O)Cl)CC2)cc1

Procedure:
0.6 g of the thus obtained trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylic acid was heated in toluene with 5 ml of thionyl chloride. Then, toluene was distilled off to obtain trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylic acid chloride. The thus obtained acid chloride was dissolved in 40 ml of carbon tetrachloride to obtain a solution, to which added were 5 ml of pyridine and a solution prepared by dissolving 0.56 g of (S)-3-hydroxy-4-(1-oxo-2-methylbutyl)phenol in 10 ml of carbon tetrachloride. The admixture was stirred at the room temperature for a day to proceed the reaction. After refluxing for additional one hour, water was added to the admixture, and the organic phase was separated. The separated organic phase was rinsed initially with a dilute hydrochloric solution, then with an aqueous solution of NaHCO3, and finally with a saturated aqueous solution of NaCl. The rinsed organic phase was dried over anhydrous Na2SO4 by allowing the same to stand for one night. The solvent was distilled off from the dried organic phase to obtain crude (S)-4-(1 -oxo-2-methylbutyl)-3-hydroxyphenyl trans-4-(4-nonyloxyphenyl)cyclohexylcarboxylate. The thus obtained crude product was recrystallized from ethanol for two times to obtain 0.04 g of a recrystallized product which was identified by infra-red absorption spectrum (IR) and nuclear magnetic resonance spectrum (NMR).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([C:12]([C:14]2[O:15][C:16]3[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[CH:19][C:17]=3[CH:18]=2)=[O:13])[CH2:11][CH2:10]1.O>C(#N)C>[Br:1][C:19]1[C:17]2[CH:18]=[C:14]([C:12]([CH:9]3[CH2:10][CH2:11]3)=[O:13])[O:15][C:16]=2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=1
Reactant: COc1cccc2cc(C(=O)C3CC3)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC#N
Product: COc1ccc(Br)c2cc(C(=O)C3CC3)oc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.3 %

Procedure:
N-bromosuccinimide (0.21 g) was added in a single portion to a stirred solution of cyclopropyl-(7-methoxybenzofuran-2-yl)-methanone (0.25 g) in acetonitrile (20 ml) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 24 h. Water (20 ml) was added, the mixture extracted with ethyl acetate (100 ml), the organic layer separated, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 5-10% ethyl acetate in hexane afforded the title compound as an off-white solid (0.24 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][C:16]=2[N+:29]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:17][C:16]=2[NH2:29])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Sc2ccc(OCc3ccccc3)cc2N)cc1
Yield: 84.2 %

Procedure:
A solution of the product of Example 214C (1.4 g, 3.09 mmol), iron powder (0.70 g, 12 mmol) and ammonium chloride (0.18 g, 3.41 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.1 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+].O1CCOCC1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncccc1-c1ccccc1
Temperature: 150 °C
Yield: 70.9 %

Procedure:
A microwave vial was charged with 2-amino-3-bromopyridine (0.5 g, 2.9 mmol), phenylboronic acid (0.52 g, 4.3 mmol), sodium bicarbonate (0.31 g, 2.9 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol), dioxane (5 mL) and water (1 mL). The vial was capped, and the reaction mixture was heated at 150° C. for 10 min. The reaction mixture was then cooled, quenched with water (10 mL), and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4) and concentrated to leave a black oil. The crude product was purified by chromatography on silica gel using 10-40% ethyl acetate/hexanes as eluant to provide the title compound as a white solid (0.35 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([CH2:10][S:11][CH2:12][C:13]([N:15]1[CH2:18][C:17]([N+:22]([O-:24])=[O:23])([N+:19]([O-:21])=[O:20])[CH2:16]1)=[O:14])[C:6]([O:8]C)=[O:7])(=[O:3])[CH3:2].[Li+].[OH-].Cl>CO.O>[C:1]([NH:4][C@@H:5]([CH2:10][S:11][CH2:12][C:13]([N:15]1[CH2:18][C:17]([N+:22]([O-:24])=[O:23])([N+:19]([O-:21])=[O:20])[CH2:16]1)=[O:14])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CSCC(=O)N1CC([N+](=O)[O-])([N+](=O)[O-])C1)NC(C)=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)N[C@@H](CSCC(=O)N1CC([N+](=O)[O-])([N+](=O)[O-])C1)C(=O)O
Temperature: 0 °C
Yield: 63.7 %

Procedure:
(R)-Methyl 2-acetamido-3-(2-(3,3-dinitroazetidin-1-yl)-2-oxoethylthio)propanoate (1.02 g, 2.80 mmol) was dissolved in methanol (50 mL) with stirring and the mixture cooled to 0° C. Then, LiOH (0.5 M, 8.40 mL) was added dropwise to the reaction mixture via a syringe and the resulting yellow mixture stirred until TLC showed complete conversion (2.5 hours). Next, the reaction mixture was diluted with water, cooled to 0° C. and acidified to pH=2 with a 50% HCl solution. Then, the reaction mixture was extracted with ethyl acetate (×2) and the extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue that was purified by column chromatography using silica gel and 30% MeOH in EtOAc as eluent to provide the title compound 625 mg (64%) as a white solid. 1H NMR (200 MHz, DMSO-d6) δ 1.85 (s, 3H), 2.81 (dd, 1H, J=8.4, 13.6 Hz), 3.04 (dd, 1H, J=4.8, 13.6 Hz), 3.33 (s, 2H), 4.41-4.35 (m, 1H), 4.80 (s, 2H), 5.13 (s, 2H), 8.20 (d, 1H, J=8.0 Hz). LC/MS (M+H=351). The purity was checked using LC/MS using Phenomenex Luna 3μ C8 (2) 100 A column using water with 0.1% TFA and acetonitrile with 0.1% as mobile phase (30-90% acetonitrile @ 1.0 mL/min). Retention time=0.60 mins; Area %=97.6%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:14]3[O:19][CH2:18][CH2:17][NH:16][CH2:15]3)[NH:12][CH:13]=2)=[CH:5][CH:4]=1.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[C:23]([NH2:28])[N:22]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([N:16]2[CH2:17][CH2:18][O:19][CH:14]([C:11]3[NH:12][CH:13]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[N:10]=3)[CH2:15]2)[N:24]=[C:23]([NH2:28])[N:22]=1
Reactant: COc1ccc(-c2c[nH]c(C3CNCCO3)n2)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)n2)cc1
Yield: 72.5 %

Procedure:
A solution of 2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}morpholine (1.9 g, 6.42 mmol), 4,6-dichloro-2-pyrimidinamine (1.053 g, 6.42 mmol) and Hunig's base (2.8 mL, 16.1 mmol) in ethanol (80 mL) was heated overnight at 85° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel chromatography using as eluent 40% EtOAc in CH2Cl2 to afford the title compound (1.8 g) as a white solid. LC-MS (ES) m/z=387 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:26][C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:33]([NH:32][C:29]2[CH:28]=[C:27]([CH3:26])[O:31][N:30]=2)=[O:34])=[CH:25][CH:24]=1)#[N:18]
Reactant: Cc1cc(NC(=O)Oc2ccccc2)no1
Reactant: COCCOc1cc2nccc(Oc3ccc(N)cc3)c2cc1C#N
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)on4)cc3)c2cc1C#N
Yield: 87.6 %

Procedure:
The 4-(4-aminophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) synthesized in Production Example 10 and phenyl N-(5-methylisoxazol-3-yl)carbamate (72 mg) were added to toluene (5 ml), and then diisopropylethylamine (0.50 ml) was added and the mixture was heated to reflux for 2 hours. After cooling, the precipitated crystals were filtered and washed with an ethyl acetate/toluene (1/1) mixed solvent to obtain the title compound (120 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32]>>[C:31]([NH:30][CH2:29][CH2:28][NH:27][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:22])(=[O:33])[CH3:32]
Reactant: CC(=O)NCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: CC(=O)NCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 39 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.056 mmol) described in example 92 and N-(2-aminoethyl)acetamide (74 mg, 0.730 mmol), was prepared N-[2-(acetylamino)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (9 mg, 39% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.39 (br s, 1 H), 8.56 (s, 1 H), 7.39 (s, 1 H), 7.17-7.15 (m, 2 H), 7.04-6.94 (m, 2 H), 6.09 (br s, 1 H), 4.13 (s, 2 H), 3.61-3.58 (m, 2 H), 3.57 (s, 3 H), 3.51-3.48 (m, 2 H), 1.98 (s, 3 H); MS m/z 413 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(Cl)cc1)C2

Procedure:
Reaction of of 6,7-dichloro-5-hydroxy-2-(p-chlorophenyl)-1-indanone with ethyl bromoacetate according to the procedure of Example 1, STEP (a), affords the title compound, m.p. 159.5°-160° (crystallized from ethanol-acetone).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:22][C@@H:23]([CH2:32]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(OCC)(=O)C>CN(C=O)C>[CH3:22][C@@H:23]([CH2:32][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=3)[CH2:14][CH2:13]2)=[CH:16][CH:17]=1)[CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)CC(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](COc1ccc(N2CCN(c3ccncc3)CC2)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (15.5 g) in dry DMF (120 ml) and the mixture was stirred for 45 minutes at room temperature. tert-Butyl (3R)-3-methyl-4-(p-toluene-sulphonyloxy)butyrate (20 g) was added and the mixture was stirred at. room temperature for 20 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separating paper (Whatman IPS) and evaporated. The residue was triturated under diethyl ether. The solid so obtained was recrystalltsed from ethyl acetate to give tert-butyl (3R)-3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (10.6 g), m.p. 112°-113° C.; [alpha]D =-5.5° (conc.=1 g/100 ml of methanol; 20° C.); NMR (CDCl3) δ 8.3(2H,d), 6.89(4H,m), 6.7(2H,m), 3.79(2H,d), 3.46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(1H,m), 1.44(9H,s), 1.07(3H,d).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1>[Ni]>[CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: [Ni]
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O

Procedure:
By adding 0.45 g of Raney nickel to 283.8 g of the thus obtained 1-isopulegol, 10 hours of hydrogenation was carried out at 70° C. under a hydrogen pressure of 2.5 MPa. By carrying out filtration and distillation of the reaction solution, 273.5 g (1.75 mol, 71.24% e.e.) of 1-menthol was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(#N)C>[CH2:1]([O:8][CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COCCC2CCC3(CC2)OCCO3)cc1
Agent: Cl
Solvent: CC#N
Product: O=C1CCC(CCOCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 8-(2-(benzyloxy)ethyl)-1,4-dioxaspiro[4.5]decane (2.30 g, 8.32 mmol) in acetonitrile (18 mL) was added 6N HCl solution and the resulting solution was stirred at rt for 2 h. After removal of acetonitrile by evaporation, the residue was neutralized by solid NaHCO3, extracted with EtOAc, dried over Na2SO4. Filtration and evaporation to dryness gave the ketone as white solid (1.84 g, 95.5%).
Reaction SMILES: [CH:1](NC(C)C)(C)C.CN(CCN(C)C)C.[Li]CCCC.[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[CH:28][S:27][C:26]=2[CH:30]=1.CI>C1COCC1.C([O-])(O)=O.[Na+]>[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[CH:29]=[C:28]([CH3:1])[S:27][C:26]=2[CH:30]=1
Reactant: CC(C)NC(C)C
Reactant: Brc1ccc2ccsc2c1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2ccc(Br)cc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
Into a stirred solution of diisopropylamine (1.45 mL, 10.3 mmol) and TMEDA (3.4 mL, 22.5 mmol) in THF (30 mL, freshly distilled) at −78° C. is added 1.6 M n-BuLi (7.0 mL, 11.2 mmol) via a syringe. The solution is warmed to 0° C. for 30 min and re-cooled to −78° C. A solution of 6-bromobenzo[b]thiophene 2.0 g, 9.38 mmol) in THF (10 mL) is added via a cannula. After stirring for 30 min, a solution of CH3I (14.0 mL, 28.1 mmol, 2.0 M in tert-butyl methyl ether) is added via a cannula. The solution is stirred overnight, while allowed to warm to room temperature, and diluted with saturated aqueous NaHCO3 (50 mL). The mixture is extracted with Et2O (3×50 mL). The organic layers are combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a tan solid (2.0177 g, 95%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:5]([N:7]1[CH2:14][CH2:13][CH2:12][C@H:8]1[C:9](O)=[O:10])=[O:6].S(Cl)(Cl)=O>C1C=CC=CC=1>[CH3:1][N:2]1[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5](=[O:6])[N:7]2[CH2:14][CH2:13][CH2:12][CH:8]2[C:9]1=[O:10]
Reactant: CNc1ccccc1C(=O)N1CCC[C@H]1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CN1C(=O)C2CCCN2C(=O)c2ccccc21

Procedure:
A mixture of 24.8 g. of (-)-1-(N-methylanthraniloyl)-proline and 300 ml. of benzene is stirred and 12.0 g. of thionyl chloride is added dropwise. The mixture is heated at reflux temperature for 2 hours, cooled, washed twice with water and concentrated to recover the (+)-1,2,3,11a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5,11(10H)-dione.
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]>CN(C)C=O>[CH3:34][O:33][C:31]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH3:7])=[C:9]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:32]
Reactant: Cc1c(-c2cccnc2)[nH]c2ccccc12
Reactant: COC(=O)CCCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21
Temperature: 25 °C

Procedure:
Dimethylformamide (1640 ml) was charged into a 20 gallon glass kettle along with 430 g of potassium t-butoxide. This solution was stirred under nitrogen and cooled to -8°. A solution of 682 g of 3-methyl-2-(3-pyridyl)indole in 3280 ml of dimethylformamide was added over 0.75 hour while the temperature is maintained below 0°. After 2 hours of stirring of -10°, 1640 ml of a solution of 780 g of methyl 8-bromooctanoate in dimethylformamide was added over 1 hour. Reaction temperature was maintained below 0°. After 2 hours stirring, the reaction mixture was allowed to warm to room temperature overnight. The rust-colored mixture was then cooled to about 5° and treated with 19.7 L of ice water. The temperature rose to 25°. After 0.5 hour stirring, the mixture was extracted with 2×8 L of ether. The extracts were dried (MgSO4) and concentrated in vacuo to give the methyl ester of 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)indole as an oil. 1293 g of this oil was treated with 6.53 L of IN NaOH and warmed over steam to 90° for 2.5 hours. After cooling to room temperature, the solution was washed with 3×3 L of ether. The aqueous layer was cooled to 10° and acidified to pH 3.5 with 3.4 L of 2N HCl. The heavy suspension which resulted was extracted with 4×4 L of methylene chloride. The combined extracts were washed once with 4 L of water and dried (MgSO4). After filtration and evaporation of solvent in vacuo at 60°, ether (1.5 L) trituration of the residue and drying gave 1-(7-carboxyheptyl)-3-methyl-2-(3-pyridyl)indole, m.p. 113°-115°. Recrystallization from ethanol raised melting point to 114°-116°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([C:19]3[NH:27][C:26]4[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=4[CH:20]=3)[CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[C:2]1([NH:1][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[C:12]([C:19]4[NH:27][C:26]5[CH2:25][CH2:24][NH:23][C:22](=[O:28])[C:21]=5[CH:20]=4)[CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(Nc5ccccc5)nc34)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A dark red mixture of aniline (0.077 ml, 0.840 mmol), 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.050 g, 0.168 mmol) and LHMDS (1.0 M solution in THF; 0.840 ml, 0.840 mmol) was sealed and stirred at RT for 1 h. The reaction was then partitioned between saturated aq. NH4Cl and DCM. The aq. layer was extracted with DCM (3×), and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting material was suspended in 1 mL MeOH, sonicated for 1 min, filtered, and rinsed 2× MeOH. The solid was dried in vacuo to give 2-(2-(phenylamino)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.035 g, 0.099 mmol, 59% yield) as a light-yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.18 (1H, br. s), 9.52 (1H, s), 8.11 (1H, d, J=9.0 Hz), 7.94 (1H, dd, J=7.4, 1.6 Hz), 7.62-7.70 (2H, m), 7.55-7.61 (1H, m), 7.36-7.45 (2H, m), 7.28 (1H, t, J=7.7 Hz), 7.04-7.14 (2H, m), 6.87-6.95 (2H, m), 3.35-3.44 (2H, m), 2.59-2.69 (2H, m). m/z (ESI, +ve) 355.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10](=O)[CH2:11][CH3:12].[N:14]([O-])=O.[Na+].Cl[Sn]Cl>OS(O)(=O)=O.O>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([Cl:8])[CH:6]=1)[NH:1][N:14]=[C:10]2[CH2:11][CH3:12]
Reactant: O=N[O-]
Reactant: CCC(=O)c1cc(Br)cc(Cl)c1N
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1n[nH]c2c(Cl)cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
1-(2-Amino-5-bromo-3-chloro-phenyl)-propan-1-one (130.0 mg, 0.50 mmol) dissolved in aqueous 50% H2SO4 (2.5 mL) and NaNO2 (43.1 mg, 0.59 mmol) was slowly added to this mixture at 0° C. The mixture was then stirred at room temperature for 1 hour. SnCl2 2H2O (342.0 mg, 1.48 mmol) was then added, and the mixture was stirred at 0° C. for 1 hour, and then diluted with water. White solid appeared and was collected by filtration and dried to afford 5-bromo-7-chloro-3-ethyl-1H-indazole as a solid (127.0 mg, 98.8%).