Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:31]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]4[CH:18]=[C:19]([S:23]([NH:26][C:27]([CH3:30])([CH3:29])[CH3:28])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=4)[N:11]3[N:10]=2)=[CH:4][CH:3]=1.[N:32]1([CH2:37][CH2:38][OH:39])[CH2:36][CH2:35][CH2:34][CH2:33]1>C(OCC)(=O)C.[Cu]I>[C:27]([NH:26][S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:11]3[N:10]=[C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([O:39][CH2:38][CH2:37][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)=[CH:3][CH:4]=4)[N:31]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH:18]=1)(=[O:25])=[O:24])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(Br)cc4)nn23)c1
Reactant: OCCN1CCCC1
Agent: [Cu]I
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 36 %

Procedure:
A solution of 3-(2-(4-bromophenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-N-tert-butylbenzenesulfonamide (150 mg, 0.3 mmol) and copper (I) iodide (57 mg, 0.3 mmol) in 2-(pyrrolidin-1-yl)ethanol (2 mL) was heated at 140° C. under a nitrogen atmosphere. After 18 hr, the reaction mixture was cooled to 20° C. and diluted with ethyl acetate (100 mL). The solution was washed with water. The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative thin layer chromatography afforded the desired product (58.5 mg, 36% yield). LCMS (ESI) m/z: 535.3. 1H NMR (400 MHz, DMSO-d6), δ: 9.44 (s, 1H), 8.64 (s, 1H), 8.21-8.19 (d, J=8 Hz, 1H), 8.10-7.99 (d, J=8 Hz, 1H), 7.78 (m, 1H), 7.66-7.57 (m, 5H), 7.24-7.22 (d, J=8 Hz, 1H), 6.90-6.88 (d, J=8 Hz, 2H), 4.15-4.10 (m, 2H), 3.20-3.10 (m, 3H), 2.89-3.05 (m, 3H), 1.83-1.79 (m, 4H), 1.11 (s, 9H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=O.[NH2:36][CH2:37][C:38]([OH:40])=[O:39].C[O-].[Na+]>>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][C:38]([OH:40])=[O:39])=[O:2])=[N:14][C:13]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:9]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(-c2ccccc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 47.5 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3,8-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), glycine (2.73 g, 36 mmol) and NaOMe solution (55 mL, 27 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified with 4 M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The solid obtained was further purified by silica gel chromatography (0-70% EtOAc/hexanes+2% AcOH) to give 36 mg of the title compound. MS: (+) m/z 506.13 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][C:10]([C:15]1[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=1)=[CH:9][C:8]2=[N:24][O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O.CC(C[AlH]CC(C)C)C.Cl>ClCCl.C1COCC1>[C:26]([O:25][N:24]=[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([CH2:3][OH:2])[CH:6]=2)[O:11][C:10]([C:15]2[N:20]=[CH:19][N:18]3[CH:21]=[CH:22][CH:23]=[C:17]3[CH:16]=2)=[CH:9]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2oc(-c3cc4cccn4cn3)cc(=NOC(C)(C)C)c2c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(CO)cc12

Procedure:
To a solution of 4-(tert-Butoxyimino)-2-pyrrolo[1,2-c]pyrimidin-3-yl-4H-chromene-6-carboxylic acid methyl ester (example 115B) (574 mg, 1.46 mmol) in dichloromethane (9 ml) at 0° C. was added a 1M solution of DIBAL-H in THF (12.8 ml). After 2 hours at 0° C. an additional amount of 1M solution of DIBAL-H in THF (6 ml) was added to complete the reaction. After hydrolysis with a 1M aqueous solution of hydrogen chloride, the reaction mixture was extracted with ethyl acetate. The organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated. The product was used without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+].II.CO>C1COCC1>[CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CNC(=O)COc1cccc2ccccc12
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCOc1cccc2ccccc12
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
At 0° C., a solution of N-methyl-2-(1-naphthyloxy)acetamide (17.4 g, 81.1 mmol) in THF (100 ml) was added dropwise to a suspension of sodium borohydride (7.35 g, 195 mmol) in THF (100 ml). The reaction mixture was stirred for 15 min at this temperature. A solution of iodine (20.6 g, 81 mmol) in THF (200 ml) was added dropwise. The reaction mixture was heated to 70° C. for 16 hours. It was cooled to 0° C. Methanol (250 ml) was added dropwise. The solvents were removed in vacuo. The residue was dissolved in a mixture of tert-butyl methyl ether (200 ml) and a 20% aqueous solution of sodium hydroxide (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The crude product was purified by flash chromatography on silica (200 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 1.94 g of N-methyl-N-[2-(1-naphthyloxy)ethyl]amine.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:22][N:21]=[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:22][N:21]=[C:20]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(Cc1cc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.4 %

Procedure:
A suspension of 3D (1.1 g, 2.18 mmol) and platinium 5% wt. on activated carbon (800 mg) in THF (80 mL) and MeOH (80 mL) was stirred at RT under H2 at 70 psi for 2 days. After this time, no starting material was detected by LC-MS. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a off-white foam (1.04 g, 94%). LC/MS (method A): retention time=3.19 min (M+H)+=506.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:2][CH2:3][CH:5]1[CH2:8][CH2:7][CH:6]1[N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:18]
Reactant: COC(=O)C1CCC1n1cnc2c(N)ncnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncnc2c1ncn2C1CCC1CO
Temperature: 0 °C
Yield: 97.1 %

Procedure:
9-(2-methoxycarbonyl-1-cyclobutyl)adenine (500 mg, 2.02 mmol) from Step A was dissolved in 250 mL of THF and the solution was cooled to 0° C. with stirring under a nitrogen atmosphere. Lithium aluminum hydride (115 mg, 3.03 mmol) was added and the reaction mixture was stirred for 30 minutes then quenched with 115 μL of water followed by 115 μL of 15% sodium hydroxide and 345 μL of water. The reaction mixture was filtered through Celite filter aid. The Celite was washed with ethyl acetate and the filtrate concentrated in vacuo to give 430 mg (97% yield) of the title compound; MS DCI-NH3M/Z: 220 (M+H)+ ; 1H NMR (d6-DMSO) δ 1.65 (m, 1H), 1.90 (m, 1H), 2.32 (m, 1H), 2.50 (m, 1H), 3.10 (m, 1H), 3.47 (t, 2H), 4.67-4.77 (m, 2H, H-1'+OH), 7.20 (bs, 2H), 8.12 (s, 1H), 8.27 (s, 1H); Analysis calculated for C10H13N5O: C, 54.78; H, 5.98; N, 31.95. Found: C, 54.79; H, 6.01; N, 31.66.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].C1(=O)[O:14][CH2:13][CH2:12]O1>[Br-].C([N+](CC)(CC)CC)C.CN(C=O)C>[OH:2][CH2:1][CH2:3][O:2][C:1]1[CH:9]=[C:7]([O:8][CH2:6][CH2:4][OH:5])[CH:6]=[C:4]([O:5][CH2:12][CH2:13][OH:14])[CH:3]=1
Reactant: O=C1OCCO1
Reactant: Oc1cc(O)cc(O)c1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: CN(C)C=O
Product: OCCOc1cc(OCCO)cc(OCCO)c1
Temperature: 150 °C
Yield: 74.3 %

Procedure:
A mixture of phloroglucinol (12.60 g, 0.10 mol), ethylene carbonate (35 g, 0.39 mol), and tetraethylammonium bromide (8 g, 0.04 mol) in DMF (20 ml,) was heated at 150° C. for 14 hr. After evaporating the solvent, the residue was purified on a silica gel chromatography column using a mixture of methylene chloride and acetonitrile: 1/1, 1/2, 1/3 and 1/4 as eluents to give 9.6 g of 1,3,5-tris(2-hydroxyethoxy)benzene (37% yield). The product was purified further by recrystallization from cold methylene chloride and THF to afford 5.5 g (21%). 1H NMR (DMSO-d6): δ 6.08 (s, aromatic protons, 3H), 4.83 (s, OH, 3H), 3.92 (t, —OCH2—, 6H), 3.69 (m, —CH2OH, 8H). 13C NMR (DMSO-d6): δ 160.54 (aromatic C—O—), 93.81 (aromatic C—H), 69.53 (—CH2O—), 59.55 (—CH2OH). FT-IR (KBr, m−1): 3255 (OH), 2947, 2371, 1596, 1462, 1377, 1167, 1071, 1024, 902, 745.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:39]=[CH:38][C:23]([CH2:24][CH:25]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:22][CH:21]=1.C(=O)(O)[O-].[Na+]>Cl.CN1C(=O)CCC1.O>[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:24][CH:25]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[C:32]([O:34][CH:35]([CH3:36])[CH3:37])=[O:33])=[CH:38][CH:39]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(=O)OC(C)C
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)OC(=O)C(Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(=O)OC(C)C
Temperature: 140 °C
Yield: 38.4 %

Procedure:
A 10-mL microwave vial was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.070 g, 0.23 mmol), diisopropyl 2-(4-aminobenzyl)malonate (0.136 g, 0.47 mmol) and conc. HCl (1 drop) in NMP (3 mL). The resulting mixture was heated at 140° C. under microwave irradiation for 2 h. After this time, the reaction mixture was cooled, diluted with water (15 mL), and then treated with saturated sodium bicarbonate until pH˜8. The resulting solid was isolated by filtration and purified by preparative HPLC (water/acetonitrile with 0.05% TFA) followed by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford diisopropyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonate (0.046 g, 38%) as an off-white solid. MW=521.05. 1H NMR (DMSO-d6, 500 MHz) δ 8.14 (s, 1H), 7.86 (s, 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H), 7.25-7.12 (m, 5H), 4.94-4.84 (m, 2H), 3.78-3.72 (m, 1H), 3.04 (d, J=7.5 Hz, 2H), 2.93-2.87 (m, 2H), 2.85-2.77 (m, 2H), 2.12-2.03 (m, 2H), 1.15 (d, J=5.5 Hz, 6H), 1.11 (d, J=5.5 Hz, 6H). MS: ESI, m/z 521 [M+H]+. Treatment with 1.25M HCl in methanol (0.11 mL, 0.13 mmol, 1.5 eq.) afforded the title compound (0.043 g, 88%) as an off-white solid. MW=557.51. M.p. 68-70° C. 1H NMR (DMSO-d6, 500 MHz) δ 13.93 (br s, 1H), 7.86-7.84 (m, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.62-7.50 (m, 2H), 7.34-7.24 (m, 4H), 6.97 (s, 1H), 4.88 (sept, J=6.0 Hz, 2H), 3.79 (t, J=7.5 Hz, 1H), 3.12-3.03 (m, 4H), 2.87 (t, J=7.5 Hz, 2H), 2.23-2.15 (m, 2H), 1.14 (d, J=5.0 Hz, 6H), 1.09 (d, J=5.5 Hz, 6H); ESI MS m/z 451 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37](Cl)=[O:38]>>[Cl:34][C:35]1[CH:43]=[CH:42][CH:41]=[CH:40][C:36]=1[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:33]=[CH:32][C:27]5[O:28][CH2:29][CH2:30][O:31][C:26]=5[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:3]=1)=[O:38]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)OCCO4)n2)c1)c1ccccc1Cl

Procedure:
{4-[2-(3-Amino-phenyl)-pyrazolo[1,5-a]pyridin-3-yl]-pyrimidin-2-yl}-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine (150 mg, 0.34 mmol) was acylated with 2-chlorobenzoyl chloride (47 μL, 0.37 mmol) in a manner analogous to Example 3 above, to give the title compound as a yellow solid. HRMS calculated C32H23ClN6O3 [M+H]+ 575.1598 found 575.1600.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]2[N:25]=[C:26]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:27][C:23]=2[CH:22]=1)[CH3:19]>O1CCCC1>[CH2:18]([O:20][C:21]1[CH:35]=[CH:34][C:24]2[N:25]=[C:26]([N:28]3[CH2:33][CH2:32][N:31]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:30][CH2:29]3)[S:27][C:23]=2[CH:22]=1)[CH3:19]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: CCOc1ccc2nc(N3CCNCC3)sc2c1
Solvent: C1CCOC1
Product: CCOc1ccc2nc(N3CCN(C(=O)c4cc(S(C)(=O)=O)ccc4OC(C)C)CC3)sc2c1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 6-ethoxy-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[O:17]=[C:18]([CH3:29])/[CH:19]=[CH:20]/[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:18]([CH:19]1[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5][CH:20]1[C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)(=[O:17])[CH3:29]
Reactant: CC(=O)/C=C/c1ccc(C#N)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1CN(Cc2ccccc2)CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.8 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (22.46 g, 94.6 mmol) in CH2Cl2 (100 mL) was added dropwise, over a 30 minutes period, to a stirred solution of 4-((E)-3-oxo-but-1-enyl)-benzonitrile (10.8 g, 63.1 mmol) and trifluoroacetic acid (0.48 mL, 6.30 mmol) in CH2Cl2 (40 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOac/Heptane 1:1) afforded 6.3 g (33%) of the title compound as a yellow oil. ES-MS m/e: 305.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11].[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)(=O)C>[C:17]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][CH:7]=[CH:6][C:5]=1[O:4][C:3]1[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=1[Cl:1])(=[O:19])[CH3:18]
Reactant: Cc1cccc(Oc2ccccc2Cl)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C)cccc1Oc1ccccc1Cl

Procedure:
A mixture of 6-(2-chlorophenoxy)-o-cresol (0.3 g), acetic acid (5 ml) and acetic anhydride (5 ml) was refluxed under heating for 7 hours. The reaction mixture was evaporated, and the oily residue was dissolved in diethyl ether, washed with an aqueous solution of sodium bicarbonate, dried over magnesium sulfate and then evaporated to give oily 2-chlorophenyl 2-acetoxy-3-methylphenyl ether (0.4 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][CH2:10][CH2:11][O:12][CH3:13].O>CN(C)C=O>[CH3:13][O:12][CH2:11][CH2:10][CH2:9][N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: c1cc[nH]c1
Reactant: COCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCn1cccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 363.9 %

Procedure:
To a solution of 1H-pyrrole (5.0 g) in N,N-dimethylformamide (40 mL) was added drop by drop sodium hydride (3.58 g) under ice-cooling, and then the mixture was stirred at room temperature for 20 minutes. Then, thereto was added dropwise a solution of 1-bromo-3-methoxypropane (2.74 g) in N,N-dimethylformamide (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water under ice-cooling, and then the mixture was extracted with diethyl ether. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=100/1→20/1) to give 1-(3-methoxypropyl)-1H-pyrrole [REx(105-1)] (9.07 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([S:15]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1ccccc1)c1cccc(Br)c1
Temperature: 55 °C
Reaction time: 19 h

Procedure:
To a 30 gallon (˜136 L) reactor was charged aniline (2) (4.01 kg; 93.13 g/mol; 43 mol), toluene (25 L), and 4-(dimethylamino)pyridine (DMAP) (12 g), and the mixture was heated to 50-60° C. 3-Bromobenzenesulfonyl chloride (1) (5 kg; 255.52 g/mol; 19.6 mol) was charged into the reactor over 30 minutes at 50-60° C. and progress of the reaction was monitored by HPLC. After 19 hours, toluene (5 L) was added due to losses overnight through the vent line and the reaction was deemed to be complete with no compound (1) being detected by HPLC. The reaction mixture was diluted with toluene (10 L) and then quenched with 2 M aqueous hydrochloric acid (20 L). The organic and aqueous layers were separated, the aqueous layer was discarded, and the organic layer was washed with water (20 L), and then 5% (w/w) sodium bicarbonate solution (20 L), while maintaining the batch temperature at 45-55° C. The batch was then used in the next synthesis.
Reaction SMILES: [CH:1]1([CH:7]([N+:23]([O-])=O)[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:11])[F:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Ni]>[NH2:23][CH:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:8]([NH:13][CH:14]([C:19]([CH3:22])([CH3:20])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])[C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)C(NC(C(C1CCCCC1)[N+](=O)[O-])C(F)(F)F)C(C)(C)C
Agent: [Ni]
Solvent: CCO
Product: COC(=O)C(NC(C(N)C1CCCCC1)C(F)(F)F)C(C)(C)C

Procedure:
Methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-nitropropan-2-ylamino)-3,3-dimethylbutanoate (5A-1) (0.553 gm) in ethanol (70 mL) was hydrogenated over Raney Nickel catalyst at 50 psi for 16 hours. The catalyst was filtered off and the filtrate was evaporated to dryness under reduced pressure, to give crude methyl 2-(3-amino-3-cyclohexyl-1,1,1-trifluoropropan-2-ylamino)-3,3-dimethylbutanoate (6). Separation by silica gel chromatography, eluting with 10% ethyl acetate/hexane, gave two pure isomers, a faster eluting compound, 6A1-isomer A (389 mgm) and a slower eluting compound, 6A1-isomer B (57 mgm). The two compounds are different stereoisomers of methyl 2-(3-cyclohexyl-1,1,1-trifluoro-3-aminopropan-2-ylamino)-3,3-dimethylbutanoate, although the absolute stereochemistry has not yet been established.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[N:6][CH:7]=1.[H-].[Na+].Br[CH:22]([CH3:28])[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24].O>CN(C=O)C>[CH:25]1([C:23](=[O:24])[CH:22]([N:6]2[CH:7]=[C:2]([I:1])[CH:3]=[CH:4][C:5]2=[N:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH3:28])[CH2:27][CH2:26]1
Reactant: CC(Br)C(=O)C1CC1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(I)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(I)cn2C(C)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of N-(5-iodopyridin-2-yl)-4-methylbenzenesulfonamide (33.1 g) in DMF (400 ml) was added NaH (40% oil dispersion, 3.89 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Then 2-bromo-1-cyclopropylpropan-1-one (23.5 g) was added, and the resulting mixture was stirred at room temperature overnight. The mixture was poured into water, and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, and concentrated. The resulting solid was suspended in IPE, stirred for 1 h, and collected by filtration. The crude product was dissolved in EtOAc (1100 ml) at 70° C., and hexane (400 ml) was added while the temperature was maintained at 60° C. Seed crystal was added, and the mixture was stirred at the same temperature for 1 h. Additional hexane (400 ml) was added at 60° C., and the mixture was allowed to cool to room temperature overnight. The precipitate was collected by filtration, washed with hexane/EtOAc (1/1) 3 times, and dried to give the title compound (30.5 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH3:19][C:20]1[C:25]([CH2:26]Br)=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH2:26][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Cc1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2C)CCCC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.4 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-o-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.21 g (98%) of the 9-[(2-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ 7.5-7.2 (m, 4H), 7.15 (t, 1H, J=8 Hz), 7.0 (t, 1H, J=8 Hz), 6.15 (d, 1H, J=8 Hz), 5.55 (s, 2H), 3.85 (s, 3H), 2.6 (m, 2H), 2.4 (m, 2H), 2.4 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2952, 1724, 1671, 1653, 1604, 1460, 1444, 1290, 1174, and 1122. MS (ES) m/e 348.5.