Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:21])=[O:4].C[O-].[Na+].I[CH2:26][CH3:27]>CO>[CH3:1][O:2][C:3]([C:5]1([CH2:26][CH3:27])[CH2:10][CH:9]([CH2:11][CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][C:6]1=[O:21])=[O:4]
Reactant: COC(=O)C1CC(CCOCc2ccccc2)CCC1=O
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC1(C(=O)OC)CC(CCOCc2ccccc2)CCC1=O
Reaction time: 48 h

Procedure:
A mixture of 5-(2-benzyloxy-ethyl)-2-oxo-cyclohexanecarboxylic acid methyl ester in anhydrous MeOH (10 mL) was reacted with NaOMe solution (16.6 mL, 8.28 mmol) at rt for 15 min. Iodoethane (2.76 mL, 34.5 mmol) was added via syringe and the mixture was stored at rt for 48 h. Another portion of NaOMe (8.3 mmol) and EtI (35 mmol) was added and the mixture was allowed to react until the starting material was not present (by TLC). The solution was quenched with an aqueous work-up and the resultant residue was purified by chromatography to yield 5-(2-benzyloxy-ethyl)-1-ethyl-2-oxo-cyclohexanecarboxylic acid methyl ester (Intermediate K2, 1.87 g (86%). The keto-ester (Intermediate K2) was heated at 90° C. in 10% KOH (100 mL) for 10 h, then 6 h at rt. The mixture was cooled to 0° C. and acidified with HCl. The solution was warmed to 40° C. for 15 min. and then stored at rt for 2 h. The mixture was neutralized to pH 7 with NaOH and the organic material was recovered by extraction with chloroform. The resulting 4-(2-benzyloxy-ethyl)-2-ethyl-cyclohexanone (Intermediate K3) was isolated by standard work-up and used without further purification (88%). Intermediate K3 (1.36 g, 5.24 mmol) was dissolved in THF (75 mL) and treated with MeMgBr (2.62 mL, 7.9 mmol) at 0° C. and reacted at rt for 1 h. The organic material was isolated from an aqueous, acidic work-up and purified by chromatography to give 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol 1.36 g (94%). 4-(2-benzyloxy-ethyl)-2-ethyl-1-methyl-cyclohexanol (1.39 g, 5.04 mmol) and TsOH—H2O (0.48 g, 2.52 mmol) were heated to reflux in benzene (˜100 mL) for 18 h in the presence of MgSO4 (˜250 mg). After an aqueous work-up and chromatographic purification, the product [2-(3-ethyl-4-methyl-cyclohex-3-enyl)-ethoxymethyl]-benzene (Intermediate K4) was isolated as a pale yellow oil 0.912 g (71%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21](CC2C=CC=CN=2)[C:20]1=[O:38]>>[Cl:15][C:16]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:17]=1[CH2:18][N:19]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[S:22](=[O:30])(=[O:29])[N:21]([CH2:2][CH:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:20]1=[O:38]
Reactant: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1Cc1ccccn1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1N(Cc2c(F)cccc2Cl)c2ccccc2S(=O)(=O)N1CC1CCOCC1

Procedure:
The title compound (150 mg, 0.34 mmol) was prepared from (IntE1) (0.3 g, 0.88 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (0.20 g, 1.05 mmol) and K2CO3 (0.36 g, 2.60 mmol) using the methods of (128).
Reaction SMILES: C(OC([N:8]1[CH2:21][CH2:20][CH2:19][C@H:9]1[C:10]([S:12][CH2:13][CH:14]([CH3:18])[C:15](O)=[O:16])=[O:11])=O)(C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[CH3:18][CH:14]1[CH2:13][S:12][C:10](=[O:11])[C@@H:9]2[CH2:19][CH2:20][CH2:21][N:8]2[C:15]1=[O:16]
Reactant: CC(CSC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1CSC(=O)[C@@H]2CCCN2C1=O
Reaction time: 72 h

Procedure:
3-[1-(tert-butyloxycarbonyl)-L-prolylthio]-2-methylpropanoic acid (2.3 g) is dissolved in a mixture of trifluoroacetic acid (15 ml) and anisole (1.1 g). After fifteen minutes at room temperature the mixture is concentrated to dryness in vacuo and the residue triturated with ether-hexane (1:1). The insoluble material is dried in vacuo, dissolved in dichloromethane (100 ml) and added dropwise to a stirred solution of 1-cyclohexyl-3-(2-morpholino-ethyl) carbodiimide metho-p-toluene sulfonate (20 g) in 900 ml of dichloromethane under argon. The reaction mixture is stored at room temperature for three days and the dichloromethane is then removed in vacuo. The residue is dissolved in ethyl acetate and the solution is washed with 10% potassium biculfate, water, saturated sodium bicarbonate and water. The organic layer is dried and concentrated to give the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][C:32]=1[N:33]([CH3:44])[C:34](=[O:43])[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:32]([N:33]([CH3:44])[C:34](=[O:43])[CH2:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:27]([O:26][CH3:25])[CH:28]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1N(C)C(=O)CCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N(C)C(=O)CCc1ccccc1
Temperature: 85 °C

Procedure:
A solution of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.293 g, 0.664 mmol) in ethylene glycol dimethyl ether (10 mL) was treated with 3-methoxy-4-[methyl(3-phenylpropanoyl)amino]phenylboronic acid (0.290 g, 0.730 mmol), tetrakis(triphenylphosphine)palladium (0.046 g, 0.040 mmol), and a solution of sodium carbonate (0.169 g, 1.59 mmol) in water (5 mL). The reaction mixture was stirred over night at 85° C. under a nitrogen atmosphere. The solvent was removed under reduced pressure, and ethyl acetate was added to the aqueous layer. The layers were partitioned, and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 4% methanol in dichloromethane, 8% methanol in dichloromethane, and then 12% methanol in dichloromethane as eluent. A second column using a Supelco flash chromatography silica gel column using 30% methanol in dichloromethane afforded 0.037 g (10%) of cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide. 1H NMR (CDCl3, 400 MHz) δ 8.374 (s, 1H), 7.315-7.312 (m, 1H), 7.285-7.213 (m, 3H), 7.174-7.087 (m, 4H), 5.795 (br. s., 2H), 4.965-4.922 (m, 1H), 3.892 (s, 3H), 3.213 (s, 3H), 2.948-2.918 (m, 2H), 2.667 (m, 6H), 2.455-2.349 (m, 10H), 2.25-2.15 (m, 2H), 1.867-1.845 (m, 2H), 1.718-1.710 (m, 2H); HPLC Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 4.947 min (98%).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:15][C:16]#[N:17])[CH:6]=[CH:7][C:8]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:18]([O:20][C:21](=[O:24])[CH:22]=[CH2:23])[CH3:19].C(O)(=O)C>C(O)C.O>[CH2:18]([O:20][C:21](=[O:24])[CH2:22][CH2:23][CH:15]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:3]([Cl:2])[CH:4]=1)[C:16]#[N:17])[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: N#CCc1ccc(C2CCCCC2)c(Cl)c1
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCC(C#N)c1ccc(C2CCCCC2)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 2.5 g of sodium in 50 ml of ethanol there is added dropwise a mixture of 23.4 g of 3-chloro-4-cyclohexyl-phenylacetonitrile and 10 g of acrylic acid ethyl ester. The solution is boiled overnight and then poured into a mixture of 10 ml of glacial acetic acid and 150 ml of water. The ethanol is evaporated and the residue distilled in a high vacuum to obtain 4-(3-chloro-4-cyclohexylphenyl)-4-cyano-butyric acid ethyl ester boiling at 200°-203°C under a pressure of 0.35 mm of Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[F:17])(=[O:26])=[O:25])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1F

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-amino-5-chloro-phenyl)phenyl-methanone and 2-fluoro-benzenesulfonyl chloride. 1H NMR (CDCl3): δ (ppm): 6.88-6.93 (m, 1H), 7.16-7.20 (m, 1H), 7.38 (d, J=6.4 Hz, 1H), 7.41-7.46 (m, 4H), 7.52 (m, 2H), 7.58-7.62 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.81-7.85 (m, 1H), 10.10 (s, 1H). MS: m/z 390.0 (M++1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([CH3:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:58])=[C:36]([CH3:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(C)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 3.5 h
Yield: 84.3 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.95 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.42 g) at: room temperature under ice-cooling and the mixture was stirred for 3.5 hours. An aqueous solution of sodium thiosulfate was added to the mixture, the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methylphenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.82 g) as colorless crystals.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30])=[CH:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1.C(OCC)(=O)C.CC(C)=O>CO.[Pd]>[ClH:1].[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][C@@H:17]([C:21]([OH:23])=[O:22])[CH2:16]1
Reactant: Cc1ccccc1C(=CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Agent: [Pd]
Agent: Cl
Solvent: CC(C)=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccccc1C(CCOCCN1CCC[C@@H](C(=O)O)C1)c1ccccc1C
Yield: 66.8 %

Procedure:
The acid prepared in Example 32 (1.1 g, 2.6 mmol) was dissolved in methanol (25 ml) and stirred under an atmosphere of hydrogen for 1 h at room temperature in the presence of 10% palladium on carbon catalyst (35% aqueous paste) and then filtered. The filtrate was evaporated to dryness leaving a residue which was treated with a mixture of ethyl acetate and acetone and filtered to give a solid which was recrystallised from a mixture of methanol and toluene to give 0.75 g (67%) of the title compound as a solid.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:3]2[CH:2]=[C:1]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:13]=1
Reactant: Nc1ccccc1
Reactant: N#CC=Cc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(Nc2cc(Nc3ccccc3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 82 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and aniline. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10].[CH:21]1([C:25](O)=[O:26])[CH2:24][CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(N(CC)CC)C>[CH:21]1([C:25]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:9]([NH:8][O:7][CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[O:10])[CH:12]=3)[CH2:17]2)=[O:26])[CH2:24][CH2:23][CH2:22]1
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Reactant: O=C(O)C1CCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)C1CCC1)C2
Reaction time: 8 h
Yield: 65.5 %

Procedure:
200 mg of N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide, 80 mg of cyclobutan carboxylic acid, 111 mg HOBT, 276 mg EDC and 0.6 ml triethylamine are dissolved in 7 ml DMF and stirred overnight. The mixture is evaporated and the residue is purified by silica gel chromatography. 170 mg of a yellowish foam are obtained.
Reaction SMILES: CNS(N(S(NC)(=O)=O)C(=O)C1C=CC=CC=1)(=O)=O.[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[O:38][C:37](=[O:39])[C:36]3[CH:40]=[C:41]([S:44]([N:47]([CH3:49])[CH3:48])(=[O:46])=[O:45])[CH:42]=[CH:43][C:35]=3[N:34]=2)[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][N:52]=1>>[C:20]([N:27]1[CH2:32][CH2:31][CH:30]([C:33]([NH:34][C:35]2[CH:43]=[CH:42][C:41]([S:44]([N:47]([CH3:48])[CH3:49])(=[O:45])=[O:46])=[CH:40][C:36]=2[C:37]([NH:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][N:52]=2)=[O:39])=[O:38])[CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: CN(C)S(=O)(=O)c1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)oc(=O)c2c1
Reactant: Nc1ccc(Cl)cn1
Agent: CNS(=O)(=O)N(C(=O)c1ccccc1)S(=O)(=O)NC
Product: CN(C)S(=O)(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1

Procedure:
Using methods substantially equivalent to those described in Example 51-D, 2-[(1-Boc-piperidin-4-ylcarbonyl)amino]-N-(5-chloropyridin-2-yl)-5-(N,N-dimethylaminosulfonylbenzamide (0.912 g, 85%) was prepared from 2-(1-Boc-piperidin-4-yl)-6-(N,N-dimethylaminosulfonyl)-4H-3,1-benzoxazin-4-one and 2-amino-5-chloropyridine.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:15]([NH:17][C:18]1([CH3:22])[CH2:21][CH2:20][CH2:19]1)=[O:16])[CH:6]=2.[Cl:27]CCl.ClN1C(=O)CCC1=O>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[Cl:27])=[CH:9][CH:8]=[C:7]([C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:15]([NH:17][C:18]1([CH3:22])[CH2:19][CH2:20][CH2:21]1)=[O:16])[CH:6]=2
Reactant: Cc1ccc(C(=O)NC2(C)CCC2)cc1-c1ccc2cc(N)ncc2c1
Reactant: ClCCl
Agent: O=C1CCC(=O)N1Cl
Product: Cc1ccc(C(=O)NC2(C)CCC2)cc1-c1ccc2c(Cl)c(N)ncc2c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 31.4 %

Procedure:
A solution of 3-(3-aminoisoquinolin-7-yl)-4-methyl-N-(1-methylcyclobutyl)benzamide (50.0 mg; 0.145 mmol) in dichloromethane (3 mL; 46.80 mmol) was treated with N-chlorosuccinimide (27.9 mg; 0.209 mmol). The reaction mixture was stirred at room temperature for 7 hours. The crude reaction mixture was filtered through a plug of silica gel, which was rinsed with ethyl acetate. The filtrate was evaporated in vacuo and the resulting residue was purified via preparatory reverse-phase HPLC and lyophilized to yield 17.3 mg (32%) of the title compound. LCMS (ESI): RT (min)=5.078, M+H=380.2, method=E; 1H NMR (400 MHz, DMSO) δ 8.92 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 6.36 (s, 2H), 2.39-2.32 (m, 2H), 2.31 (s, 3H), 2.02-1.93 (m, 2H), 1.86-1.75 (m, 2H), 1.47 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].Br[CH2:16][CH2:17][O:18][CH2:19][CH3:20]>CC#N>[CH2:17]([O:18][CH2:19][CH2:20][O:14][C:6]1[CH:7]=[C:8]([NH2:11])[CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:16]
Reactant: CCOCCBr
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1O
Solvent: CC#N
Product: CCOCCOc1cc(N)ccc1C(C)(C)C

Procedure:
3-(2-Ethoxyethoxy)-4-tert-butylbenzenamine (C-3) was synthesized following the general scheme above starting from 2-tert-butyl-5-nitrophenol (C-1-a) and 1-bromo-2-ethoxyethane. 1H NMR (400 MHz, CDCl3) δ 6.97 (d, J=7.9 Hz, 1H), 6.17 (s, 1H), 6.14 (d, J=2.3 Hz, 1H), 4.00 (t, J=5.2 Hz, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.53 (q, J=7.0 Hz, 2H), 1.27 (s, 9H), 1.16 (t, J=7.0 Hz, 3H); HPLC ret. time 2.55 min, 10-99% CH3CN, 5 min run; ESI-MS 238.3 m/z (MH+).
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:6]([CH2:21][C:22](O)=[O:23])[N:5]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[NH:48]1)=[O:46].CCCP(=O)=O.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:32][C:33]1[C:38]([O:39][C:40]([F:43])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:34]=1[NH:44][C:45]([C@@H:47]1[CH2:52][C@@H:51]2[C@@H:49]([CH2:50]2)[N:48]1[C:22](=[O:23])[CH2:21][N:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][CH:8]=2)[C:4]([C:1](=[O:3])[CH3:2])=[N:5]1)=[O:46]
Reactant: O=C(Nc1cccc(OC(F)(F)F)c1F)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: CC(=O)c1nn(CC(=O)O)c2ccc(OCc3ccccc3)cc12
Agent: CCCP(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2F)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (3-acetyl-5-benzyloxy-indazol-1-yl)-acetic acid (1.38 g, 4.30 mmol, prepared as described in Part A), (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoro methoxy-phenyl)-amide trifluoroacetate (1.80 g, 4.30 mmol) and propylphosphonic anhydride (50% in EtOAc, 3.80 ml, 6.46 mmol) in CH2Cl2 (40 ml) was added DIPEA (2.25 mL, 12.91 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was concentrated and the crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1). MS (UPLC-MS): 611 [M+H]+; tR (HPLC conditions f): 2.40 min.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH2:8]([SH:12])[CH2:9][CH2:10][SH:11]>C(Cl)Cl>[CH2:2]([CH:1]1[S:12][CH2:8][CH2:9][CH2:10][S:11]1)[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: SCCCS
Reactant: C#CCCCC=O
Solvent: ClCCl
Product: C#CCCCC1SCCCS1
Reaction time: 48 h
Yield: 72449.2 %

Procedure:
Hex-5-ynal (20 g, 0.2M) and 1,3-propanedithiol (20 mL, 0.2 mmol) were stirred in 300 mL methylene chloride at 0°-5° C. and HCl(g) was bubbled into the solution for 10 minutes when it became cloudy. The mixture was stirred 2 days after which it was poured onto 100 mL of 10% KOH. The organics were washed again with 10% KOH (25 mL), then brine, and dried (MgSO4) before evaporation at reduced pressure. The residue was Kugelrohr distilled at 0.1 mm, oven 110° C. to give 27 g of product (72%). 1H NMR (CDCl3) δ 1.7-1.8 (m, 2H), 1.8-1.95 (m, 3H), 1.99 (t, J=2.6 Hz, 1H), 2.2-2.25 (m, 2H), 2.8-2.95 (m, 4H), 4.06 (t, J=6.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH2:15][CH2:16][Cl:17])[CH:6]=2.[NH2:23][C:24]1[C:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[CH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH2:35][CH2:36][Cl:37])=[C:29]([O:38][CH3:39])[CH:28]=2.CO[CH:47](OC)[N:48]([CH3:50])[CH3:49]>>[Cl:37][CH2:36][CH2:35][O:34][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][C:29]=1[O:38][CH3:39])[CH:26]=[C:25]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:24](/[N:23]=[CH:47]/[N:48]([CH3:50])[CH3:49])=[CH:33]2.[Cl:17][CH2:16][CH2:15][O:14][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2](/[N:1]=[CH:47]/[N:48]([CH3:50])[CH3:49])[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4]2)=[CH:9][C:8]=1[O:12][CH3:13]
Reactant: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1N
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1N
Product: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1/N=C/N(C)C
Product: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1/N=C/N(C)C

Procedure:
A 648 mg portion of ethyl 3-amino-7-(2-chloroethoxy)-6-methoxy-2-naphthoate and ethyl 3-amino-6-(2-chloroethoxy)-7-methoxy-2-naphthoate (1:1 mixture) and 5 mL of dimethylformamide dimethylacetal is heated to reflux using an oil bath. The reaction is kept at reflux overnight. Solvent is removed in vacuo to provide crude ethyl 6-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]amino}-7-methoxy-2-naphthoate and ethyl 7-(2-chloroethoxy)-3-{[(E)-(dimethylamino)-methylidene]amino}-6-methoxy-2-naphthoate (1:1 mixture) as a dark red mixture.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[Cl:16])O)[CH:2]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl>[ClH:15].[Cl:19][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16]
Reactant: O=S(Cl)Cl
Reactant: OC(c1cccnc1)c1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Product: Cl
Product: Clc1ccc(C(Cl)c2cccnc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 100 ml Erlenmeyer flask equipped with a reflux condensor is added 2.54 gm of 3-pyridyl-2,4-dichlorophenylcarbinol and 30 ml of chloroform. The system is cooled to 0° C. and 1.31 gm (1.2 equivalents) of thionyl chloride in 25 ml of chloroform is added over 1/2-hour. After addition of the thionyl chloride, the system is allowed to come to room temperature and stirred there for 2 hours. The system is then heated at reflux for 1 hour. The chloroform is removed by stripping to give the alpha-chloro-alpha-(3-pyridyl)-2,4-dichlorotoluene hydrochloride salt.