Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:28])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>O>[C:5]([Cl:3])(=[O:28])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Temperature: 45 °C
Reaction time: 1.17 h

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 7.88 ml (108 mmol) of thionyl chloride, and a water condenser, is placed 20.44 g (60 mmol) of docosanoic acid. Addition of the thionyl chloride is completed with heating to about 45° C. over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 70 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloride, docosanoyl chloride. This acyl chloride, 21.60 g (60 mmol), is put into a dry separatory funnel and combined with 100 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=2)=[CH:5][N:4]=[N:3]1.C1C(=O)N([Cl:23])C(=O)C1>CN(C)C=O.CCOC(C)=O>[Cl:23][C:5]1[N:4]=[N:3][N:2]([CH3:1])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[S:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2cnnn2C)cs1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2c(Cl)nnn2C)cs1
Yield: 79.7 %

Procedure:
A solution of methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)-2-thiophenecarboxylate (500 mg, 2.24 mmol) and NCS (1196 mg, 8.96 mmol) in N,N-Dimethylformamide (DMF) (10 ml) was heated at 50° C. for 2 hr. The reaction mixture was diluted with 50 ml of EtOAc. The organic layer was washed with H2O (50 ml×2) and brine (50 ml), and then concentrated to give 460 mg of a crude mixture, which was used in next step without further separation. LCMS (ES) m/z 258.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[O:12][CH2:13][C:14]([CH3:17])([CH3:16])[N:15]=1.[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>>[CH3:16][C:14]1([CH3:17])[CH2:13][O:12][C:11]([C:3]2[CH:4]=[C:5]3[O:10][CH2:9][O:8][C:6]3=[CH:7][C:2]=2[C:22]2([OH:25])[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)=[N:15]1
Reactant: CC1(C)COC(c2cc3c(cc2Br)OCO3)=N1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(O)(c2cc3c(cc2C2=NC(C)(C)CO2)OCO3)CC1

Procedure:
Reaction of 2-(2-bromo-4,5-methylenedioxyphenyl)-4,4-dimethyl-2-oxazoline and 1methyl-4-piperidone by the method described in Example 1c provides 4-[2-(4,4-dimethyl-2-oxazolin-2-yl)-4,5-methylenedioxyphenyl]-4-hydroxy-1-methylpiperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][C:22]([C:24]1([CH3:27])[CH2:26][O:25]1)=[O:23]>>[Cl:1][C:2]1[CH:9]=[C:8]([CH:7]=[CH:6][C:3]=1[C:4]#[N:5])[O:10][CH2:27][C:24]([OH:25])([CH3:26])[C:22]([NH:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[CH3:11])=[O:23]
Reactant: Cc1cc([N+](=O)[O-])ccc1NC(=O)C1(C)CO1
Reactant: N#Cc1ccc(O)cc1Cl
Product: Cc1cc([N+](=O)[O-])ccc1NC(=O)C(C)(O)COc1ccc(C#N)c(Cl)c1

Procedure:
3-(3-Chloro-4-cyanophenoxy)-2-hydroxy-2-methyl-N-(2-methyl-4-nitrophenyl)propionamide was prepared as described in Example 64c starting from 2-chloro-4-hydroxybenzonitrile and 2-methyloxirane-2-carboxylic acid (2-methyl-4-nitrophenyl)amide. The crude product was purified by flash chromatography (dichloromethane-1.3% methanol). 1H NMR (400 MHz, DMSO-d6): 1.46 (3H, s), 2.37 (3H, s), 4.15 (1H, d, J=10.1 Hz), 4.39 (1H, d, J=10.1 Hz), 6.51 (1H, s), 7.10 (1H, dd, J=8.8 Hz, J=2.4 Hz), 7.37 (1H, d, J=2.4 Hz), 7.86 (1H, d, J=8.8 Hz), 8.05-8.12 (2H, m), 8.18 (1H, d, J=2.3 Hz), 9.56 (1H, s).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=2)=[N:13]1
Reactant: COC(=O)c1ccc(C#N)nc1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 57.2 %

Procedure:
A mixture of methyl thiosalicylate (2.1 g, 12.3 mmol), methyl 6-cyanonicotinate (2.0 g, 12.3 mmol), triethylamine (3.0 ml, 21.5 mmol) and toluene (6 ml) was refluxed for 12 hrs as described in Example 1. The precipitated crystals were collected by filtration and recrystallized from diisopropylether-chlorobenzene to give the titled compound (2.1 g, 58%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][C:16]=2[CH2:25][CH:26]([CH3:28])[CH3:27])[CH:12]=[CH:11][C:10]=1[C:29]1[CH:34]=[CH:33][C:32]([O:35]C)=[C:31]([CH2:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[CH:40][CH:39]=2)[CH:30]=1)[CH:6]([CH3:8])[CH3:7].O>C(Cl)Cl>[OH:35][C:32]1[CH:33]=[CH:34][C:29]([C:10]2[CH:11]=[CH:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]#[N:24])=[CH:17][C:16]=3[CH2:25][CH:26]([CH3:27])[CH3:28])=[CH:14][C:9]=2[CH2:5][CH:6]([CH3:8])[CH3:7])=[CH:30][C:31]=1[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(-c2ccc(-c3ccc(CCC#N)cc3CC(C)C)cc2CC(C)C)cc1Cc1cccc2ccccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)Cc1cc(CCC#N)ccc1-c1ccc(-c2ccc(O)c(Cc3cccc4ccccc34)c2)c(CC(C)C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 61.8 %

Procedure:
1.02 ml (1.02 mmol, 3.00 eq.) of a 1 M solution of BBr3 in CH2Cl2 was added to a solution of 192.9 mg (0.34 mmol) 3-(2′,2″-Diisobutyl-4-methoxy-3-naphthalen-1-ylmethyl-[1,1′:4′, 1″]-terphenyl-4″-yl)propionitrile (76) in 20 ml dry CH2Cl2 at 0° C. via syringe. After that the solution was stirred for 3 h at 0° C. and then for 12 h at r.t. The reaction mixture was then added to water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (hexanes/EtOAc (2+1)) yielded 117.9 mg (0.21 mmol, 62.85%) 3-(4-Hydroxy-2′,2″-diisobutyl-3-naphthalen-1-ylmethyl-[1,1′:4′, 1″]terphenyl-4″-yl)propionitrile (32) as a colorless oil. Rf (hexanes/EtOAc (2+1))=0.37. 1H-NMR (500 MHz, CDCl3): δ=0.59 (d, 6H, J=6.62 Hz, 2*CH3), 0.70 (d, 6H, J=6.78 Hz, 2*CH3), 1.50 (m, 1H, CH), 1.65 (m, 1H, CH), 2.32 (d, 2H, J=7.25 Hz, CH2), 2.47 (d, 2H, J=7.25 Hz, CH2), 2.62 (t, 2H, J=7.41 Hz, CH2CH2CN), 2.94 (t, 2H, J=7.41 Hz, CH2CH2CN), 4.47 (s, 2H, CH2Naphthyl), 4.80 (s, 1H, OH), 6.86 (d, 1H, J=8.36 Hz), 6.98-7.16 (m, 9H), 7.38 (m, 1H), 7.43-7.48 (m, 2H), 7.73 (dm, 1H, J=8.73 Hz), 7.83 (m, 1H), 8.06 (m, 1H). MS (EI): m/z=552 (30), 551 (65), 446 (21), 419 (21), 178 (19), 155 (15), 149 (24), 142 (18), 141 (100), 128 (28), 97 (23), 85 (26), 83 (25), 71 (39), 69 (30), 57 (74), 55 (35). HR-MS (EI): Calcd. for C40H41NO: 551.318814. Found: 551.318768.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][C:6](N)=[O:7])C.[C:10]1([NH:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N>C1(C)C(C)=CC=CC=1>[C:18]1([N:17]2[C:6](=[O:7])[NH:5][C:4](=[O:3])[N:16]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(NNc2ccccc2)cc1
Reactant: CCOC(=O)NC(N)=O
Agent: N
Solvent: Cc1ccccc1C
Product: O=c1[nH]c(=O)n(-c2ccccc2)n1-c1ccccc1

Procedure:
50 g (0.378 Mol) of ethylallophanate and 76.6 g (0.416 Mol) of 1,2-diphenylhydrazine were suspended in 100 ml of anhydrous xylene and refluxed for 6 hours with stirring, during which time ammonia was released. The solvent was distilled off, the residue was mixed with 150 ml of xylene once more and refluxed for 1 hour. The mixture was left to cool, the reaction product was suction filtered, and thoroughly washed with cold xylene. After drying in vacuo, 60.0 g (63% of theory) of colourless crystals were obtained, mp. 216°-217° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.Cl.[CH3:13][C:14]1[C:15]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH:19]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:25]2[CH2:26][CH2:27][N:22]([C:15]3[C:14]([CH3:13])=[CH:19][C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=3)[CH2:23][CH2:24]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(Cl)c1ccc(Br)cc1F
Agent: Cl
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Yield: 59.5 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 8 and using 4-bromo-2-fluorobenzoyl chloride (5 g) and 1-(3,5,6-trimethylpyridin-2-yl)piperazine hydrochloride (5 g) described in Preparation Example 52, the title compound (5 g) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:18][CH2:19][C:20](O)=O)C1C=CC=CC=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[CH3:44][O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:54][CH2:53][CH:52]([CH2:55][NH2:56])[O:51][C:50]=2[CH:57]=1.Cl>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:54][CH2:53][CH:52]([CH2:55][NH:56][CH2:20][CH2:19][CH2:18][C:12]3[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([OH:8])[CH:10]=4)[NH:14][CH:13]=3)[O:51][C:50]=2[CH:57]=1
Reactant: COc1ccc2c(c1)OC(CN)CO2
Reactant: O=C(O)CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)OC(CNCCCc1c[nH]c3ccc(O)cc13)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
5-Benzyloxyindole-3-propionic acid (1.8 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 7-methoxy-2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.0 hydrochloride (1.4 g, 6.0 mmole) in 50 ml of DMF and the mixture was further stirred for 48 hours. The solvent was removed and replaced with dichloromethane. The mixture was then washed with H2O. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel using first dichloromethane and then 2.5% methanol in dichloromethane as eluants to give 2.6 g (90%) of the desired product, (7-methoxy-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-(5-benzyloxy-1H-indol-3-yl)-propanamide, as a light tan solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O.[BH4-].[Li+]>CCOCC>[CH3:11][C:7]1([CH3:10])[N:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@H:5]([CH2:3][OH:2])[CH2:9][O:8]1
Reactant: CCCCCCC(=O)N1[C@H](C(=O)OC)COC1(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](CO)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8a (296 mg, 1.09 mmol) in dry ether (1 mL) is treated with lithium borohydride (2M solution in THF, 0.55 mL, 1.09 meq) under an argon atmosphere. The mixture is stirred for 3 h at reflux and 18 h at room temperature. The resulting mixture is diluted with ether and quenched with methanol. The volatiles are removed and the residue is taken up in EtOAc/H2O. Workup provides the crude alcohol which is purified by chromatography (2:1 hexane/EtOAc): NMR δ 0.88 (m, 3H), 1.30 (m, 6H), 1.54 (s, 3H), 1.62 (s, 3H), 2.35 (m, 2H), 3.30-4.40 (complex m, 6H); MS (HR-E1) m/z 243.1837 (M calcd. for C13H25NO3 243.1840); [α]D26 =-5±1 (CHCl3).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+].O>CO.O>[N:14]([CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:6]=2[O:5][CH:4]=1)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cccc2c(CBr)coc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc2c(CN=[N+]=[N-])coc12
Temperature: 25 °C
Yield: 94.9 %

Procedure:
3-bromomethyl-7-methoxybenzofuran (565 mg) and sodium azide (230 mg) were dissolved in methanol-water (5:1, 10 ml) and the solution was refluxed for 1 hour. After cooling the reaction solution to room temperature, the reaction solution was poured into water layer (30 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing sodium sulfate, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=9/1) using silica gel to obtain the desired compound (452 mg, yield: 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].I[CH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C1OCCOCCOCCOCCOCCOC1>C(#N)C>[CH:23]1([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH2:12]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: IC1CCCC1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCN(C3CCCC3)CC2)cc1

Procedure:
A mixture of 1-(4-nitrophenyl)piperazine (12 g, 57.9 mmol) (Acros Organics), powdered potassium carbonate (5.4 g, 39 mmol), iodocyclopentane(7 mL, 60.8 mmol) (Aldrich) and a catalytic amount of 18-crown-6 in acetonitrile (90 mL) was heated at reflux overnight. The mixture was filtered, and the filter cake was washed with acetonitrile. The solvent was evaporated from the combined filtrates and the residue was partitioned between water and ethyl acetate. The layers were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, evaporated to a yellow solid and dried under vacuum to give 1-cyclopentyl-4-(4-nitrophenyl)piperazine) (6.6 g, 41%.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].CC[O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([C:13]([OH:12])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:20]=[N:6]2)=[CH:8][CH:9]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(N)c1
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(OC)ccc2c1O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of m-methoxyaniline (35 g, 0.28 mol) and diethyl ethoxymethylene malonate (74 g, 0.34 mol) was stirred 2 h at 110° C. under reduce pressure. The mixture was heated at 240° C. under reduced pressure for an additional 2 h. The resulting solid was suspended in CH2Cl2, filtered off and washed with CH2Cl2 to yield 7-methoxy-4-hydroxy-3-ethoxycarbonylquinoline as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:16])[C:6]([C:17]#[N:18])=[C:5]([Cl:19])[CH:4]=1.[C:20]([O-:23])(=[O:22])[CH3:21].[Na+].O>CC(C)=O>[C:20]([O:23][CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7](=[O:16])[C:6]([C:17]#[N:18])=[C:5]([Cl:19])[CH:4]=1)(=[O:22])[CH3:21]
Reactant: N#Cc1c(Cl)cc(CBr)n(-c2ccccc2Cl)c1=O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)OCc1cc(Cl)c(C#N)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.5 %

Procedure:
To a solution of 6-(bromomethyl)-4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step F (1.53 g) in acetone (42.7 mL) was added sodium acetate (1.75 g) at room temperature. The reaction mixture was stirred at 70° C. for 8 hr, and cooled to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (670 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:26]=[N+:27]=[N-].[Na+].C(OCC)C>FC(F)(F)C(O)=O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=2)=[N:10][C:9]([Br:21])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:26]=[N-:27]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)nc(-c2ccc(OC)c(Cl)c2)c1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Methyl 3-amino-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (181 mg, 0.487 mmol) was dissolved in trifluoroacetic acid (2.4 mL) and cooled in an ice bath. Solid sodium nitrite (67 mg, 0.97 mmol) was added with stirring to give a dark red mixture. After 10 minutes, solid sodium azide (317 mg, 4.87 mmol) was added followed by diethyl ether (2.4 mL). This was stirred in the ice bath for 10 minutes and then partitioned between EtOAc and sufficient saturated aqueous NaHCO3 solution (gas evolution) to neutralize the acid. The organic phase was separated, washed with brine, dried with sodium sulfate, and the solvent removed. The gave methyl 3-azido-6-bromo-2-(3-chloro-4-methoxyphenyl)isonicotinate (161 mg) as a yellow solid. MS (ESI) m/z 398.9 (M+H). 1H NMR (CDCl3) δ ppm 7.85 (1H, d, J=2.14 Hz), 7.75 (1H, s), 7.71 (1H, dd, J=8.55, 2.14 Hz), 7.01 (1H, d, J=8.55 Hz), 4.01 (3H, s), 3.96 (3H, s).
Reaction SMILES: [CH2:1]([C:8]([N:10]1[CH2:18][CH2:17][N:16]([C:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=O)[CH2:15][CH2:14][N:13]([C:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=O)[CH2:12][CH2:11]1)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].B.C1COCC1.[OH-].[Na+]>CO>[CH2:8]([N:10]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:15][CH2:14][N:13]([CH2:28][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:12][CH2:11]1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCC(=O)N1CCN(C(=O)CCCCCCC)CCN(C(=O)CCCCCCC)CC1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCN1CCN(CCCCCCCC)CCN(CCCCCCCC)CC1
Temperature: 25 °C
Yield: 85 %

Procedure:
All of the 1,4,7-tri(n-heptylcarbonyl)-1,4,7-triazacyclononane was put into a 200 mL three neck flask provided with a reflux tube in an argon atmosphere, and a BH3.THF solution (100 mmol, 100 mL) was added thereto and reflowed for one night. To break down the excess BH3.THF, methanol was added slowly to the reaction mixture after allowing it to cool to room temperature, and after concentration, this was dissolved in 1-butanol (50 mL), water (50 mL) and concentrated hydrochloric acid (100 mL and reflowed for one night. The reaction mixture obtained was cooled in an ice bath, and a 48% aqueous solution of sodium hydroxide was added until the pH exceeded 12. After amine separation, this aqueous solution was extracted in methylene chloride (8×50 mL). After the organic layer that was obtained was dried using anhydrous sodium sulfate, it was concentrated, and pale yellow, oily 1,4,7-tri-n-octyl-1,4,7-triazacyclononane (2.45 g, 85% yield) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:3]=1[NH2:4].[CH3:11][S:12][CH3:13].ClN1C(=O)CCC1=O.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([NH2:4])=[C:5]([CH2:11][S:12][CH3:13])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1
Reactant: CSC
Reactant: Nc1cc(F)c(F)cc1Br
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSCc1c(N)c(Br)cc(F)c1F

Procedure:
To a solution of 2-bromo-4,5-difluoroaniline (100 g) and dimethyl sulfide (49 ml) in anhydrous dichloromethane (1.2 liter) is added gradually N-chlorosuccinimide (90 g) at below 15° C., and thereafter is further added in portions triethylamine (93 ml) at 15° C. After the addition, the mixture is refluxed for 7 hours. After cooling, 10% aqueous sodium hydroxide (one liter) is added to the reaction mixture, and the mixture is extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated, and the resulting residue is purified by silica gel column chromatography (solvent, dichloromethane:n-hexane=1:2). The product is recrystallized from n-hexane to give 6-bromo-3,4-difluoro-2-methylthiomethylaniline (52 g) as a white crystal, m.p. 60°-61° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([O:36][C:37]([F:40])([F:39])[F:38])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([O:36][C:37]([F:40])([F:38])[F:39])[CH:35]=[C:30]([OH:29])[CH:31]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: OB(O)c1cc(O)cc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(OC(F)(F)F)c3)n(-c3ccccc3)c(=O)c12
Yield: 50.9 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (82 mg, 0.19 mmol) was treated with 3-hydroxy-5-(trifluoromethoxy)phenylboronic acid (124 mg, 0.56 mmol), sodium carbonate (2M, 375 μl, 0.75 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (15 mg, 0.02 mmol) according to the method described in Example 3 to give 52 mg (51% yield) of the title compound. Purity 98%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][CH2:8]2)([O-:3])=[O:2].C(O)(=[O:15])C>[O-2].[Cr+6].[O-2].[O-2]>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][C:8]2=[O:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1CCC2
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: [O-2]
Product: O=C1CCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A suspension of chromium(VI) oxide (36.7 g, 367.7 mmol) in acetic acid (400 mL) was added slowly to a solution of 4-nitroindane (20 g, 122.6 mmol) in glacial acetic acid (500 mL). Extra acetic acid (200 mL) was used to transfer all the chromium(VI)oxide. The reaction was stirred vigorously at room temperature for about 5 hours and was then quenched with water (200 mL). Most of the acetic acid was removed under high vacuum and the crude product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using first hexane/ethyl acetate (20:1) as eluent to remove unreacted starting material and then hexane/ethyl acetate (10:1) to provide the desired product. MS (ESI): m/z 176 (M−H)−.