Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:5]=2[C:4](O)=[N:3][CH:2]=1.O=P(Cl)(Cl)[Cl:16].[OH-].[NH4+]>>[Cl:16][C:4]1[C:5]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: Oc1ncnc2c1CCCCCC2
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ncnc2c1CCCCCC2
Temperature: 100 °C
Yield: 98 %

Procedure:
A mixture of 5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (0.66 g; 3.7 mmol; 1.0 equiv) in 3.3 mL of POCl3 (37 mmol; 10 equiv) was heated at 100° C. for 2 hours. The reaction was cooled and poured onto ice. The solution was adjusted to ca. pH 5 with ammonium hydroxide. The oil was extracted with ether and the extract was dried over MgSO4. The solvent was evaporated to give 4-chloro-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine t as a clear yellow oil (0.71 g; 98% yield).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([C:16](=[O:29])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(Cl)([C@@H]1[C@@H](C)[C@H]2C(C)(C)[C@@H](C2)C1)[C@@H]1[C@@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1>C1COCC1>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:29])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(CCC(=O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Agent: C[C@@H]1[C@@H](B(Cl)[C@H]2C[C@@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@@H]2C[C@H]1C2(C)C
Solvent: C1CCOC1
Product: COc1ccc(CCC(O)c2cccc(OCC(=O)OC(C)(C)C)c2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.2 %

Procedure:
A solution of 1-(3-(tert-Butoxycarbonylmethoxy)phenyl)-3-(3,4-dimethoxyphenyl)propan-1-one (10) (3.0 g, 7.49 mmol) in THF (5 mL) at -20° C. was treated with a solution of (+)-B-chlorodiisopinocamphenylborane (2.9 g, 8.99 mmol) in THP (10 mL) at -20° C. The resulting mixture was allowed to stand in a -20° C. freezer for 48 h after which time the mixture was evaporated and treated with diethyl ether (25 mL) followed by diethanolamine (8 mL). The viscous mixture was allowed to stir at room temperature for 3 h, after which time, was filtered through a pad of Celite with the aid of diethyl ether. The cloudy filtrate was evaporated and flash chromatographed (silica gel, 30% 40% EtOAc/hexanes) to afford 2.72 g (90%) of a clear colorless oil. (95% ee by Chiracel HPLC, 25% i-PrOH/hexanes, retention time 44A min for the R-enantiomer and 35.7 min for the S-enantiomer): IR (neat) 3525, 2935, 1750, 1515, 1150 cm-1 ; 1H NMR (CDCl3, 300 MHz) 7.30-7.25 (m, 2H), 6.99-6.73 (m, 5H), 4.68 (m, 1H), 4.53 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 2.72-2.63 (m, 2H), 2.12-1.97 (m, 2H), 1.50 (s, 9H); 13C NMR (CDCl3, 75 MHz) 168.4, 158.5, 149.3, 147.6, 146.9, 134.8, 130.0, 120.6, 119.5, 114.0, 112.6, 112.2, 111.7, 82.7, 74.1, 66.1, 56.3, 56.2, 41.0, 32.0, 28.4.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])C.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH:31][C:8]2[C:9](=[O:10])[N:5]([CH:1]([CH3:3])[CH3:4])[S:6](=[O:18])(=[O:19])[C:7]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COc1ccc(CCN)cc1Cl
Product: COc1ccc(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1Cl

Procedure:
The title compound was prepared from 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3-chloro-4-methoxyphenyl)ethyl]amine in a similar manner as described for Example 24. 1H NMR (500 MHz DMSO-d6): δ 7.55-7.47 (m, 5H), 7.34 (t, 1H), 6.94 (d, 1H), 6.65 (dd, 1H), 6.61 (d, 1H), 4.32 (qt, 1H), 3.78 (s, 3H), 3.03-2.96 (m, 2H), 2.43-2.37 (m, 2H), 1.46 (d, 6H); 13C NMR (125 MHz DMSO-d6): δ 158.7, 153.7, 136.1, 132.4, 131.9, 130.3, 129.4, 128.8, 126.1, 121.3, 113.3, 105.0, 56.7, 47.3, 45.0, 34.4, 20.5; Mass spectrum M+H+ 435
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:51]3[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (47 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). This solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (238.7 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky solid [73 mg (60%)]. LC-MS m/z 754.3 (M+H)+.
Reaction SMILES: O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)C(C)C)(C)C.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[CH:31][CH:30]=2.[C:36]([O:40][C:41]([NH:43][C@@H:44]([C:53](O)=[O:54])[CH2:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:42])([CH3:39])([CH3:38])[CH3:37]>ClCCl>[N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[C:26]([NH:25][C:53](=[O:54])[C@@H:44]([CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:43][C:41]([O:40][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:42])[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Reactant: Nc1cnc2ccccc2c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 73.9 %

Procedure:
Bis(2-oxo-3-oxazolidinyl)phosphinic chloride (829 mg) and N,N-diisopropylethylamine (1.13 mL) were added to a solution of 3-aminoquinoline (391 mg) and N-tert-butoxycarbonyl-D-homophenylalanine (1.13 g) in dichloromethane (15 mL) at 0° C. After stirring at 0° C. for 10 min and at room temperature for 19 hr, the solvent was removed in vacuo. The residue was diluted with 10% citric acid and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate, and brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform then chloroform: methanol=50:1, v/v) to afford the title compound (813 mg) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.00-2.10 (m, 1H), 2.27-2.39 (m, 1H), 2.80 (t, J=7.8 Hz, 2H), 4.20-4.29 (m, 1H), 4.98-5.07 (m, 1H), 7.19-7.33 (m, 5H), 7.51-7.55 (m, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), and 8.68-8.80 (m, 3H).
Reaction SMILES: [I-:1].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1.O1CCOCC1.CNCCNC>[Cu]I.CN(C=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([I:1])=[CH:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=1
Reactant: Nc1nccc(Nc2cc(Br)ccc2N)n1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Nc1nccc(Nc2cc(I)ccc2N)n1
Temperature: 115 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A pressure tube containing copper(I) iodide (61.2 mg, 0.32 mmol), sodium iodide (963.18 mg, 6.43 mmol) and 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (900 mg, 3.21 mmol) was flushed with nitrogen before the addition of 1,4-dioxane (4.0 mL), DMF (4.0 ml) and N,N′-dimethylethane-1,2-diamine (0.035 ml, 0.32 mmol). The vessel was sealed and stirred at 115° C. overnight. After cooling to RT, the reaction mixture was poured into ice water (7 ml) and the resulting solution extracted with DCM (2×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification by column chromatography (Biotage, 3-14% methanol gradient in DCM) furnished the title compound (600 mg, 57% yield); 1H NMR (500 MHz, DMSO) delta 5.04 (2H, d, J=11.6 Hz), 5.78-5.73 (1H, m), 6.11-6.02 (2H, m), 6.57 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4, 2.0 Hz), 7.47-7.38 (1H, m), 7.75 (1H, d, J=5.3 Hz), 8.20-8.12 (1H, m); LC-MS: m/z=+327.8 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>>[CH2:17]([O:16][C:12](=[O:15])[CH2:13][CH2:14][N:1]1[CH2:11][CH2:10][CH2:9][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[CH3:18]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Temperature: 80 °C

Procedure:
A 25 mL round-bottom flask was charged with ethyl nipecotate (4.0 mL, 25.7 mmol, Aldrich) and ethyl acrylate (3.4 mL, 31.4 mmol; Aldrich). The flask was purged with nitrogen and the mixture was heated to 80° C. for 20 hours, then purified by silica gel chromatography (ethyl acetate-dichloromethane-triethylamine 50:50:1; Rf=0.28) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.23-1.28 (m, 6H), 1.42-1.59 (m, 2H), 1.68-1.74 (m, 1H), 1.89-1.95 (m, 1H), 2.01-2.08 (m, 1H), 2.17-2.24 (m, 1H), 2.46-2.56 (m, 3H), 2.68-2.76 (m, 3H), 2.94-2.99 (m, 1H), 4.09-4.17 (m, 1H); MS (DCI/NH3) m/z 258 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[C:10]=3[N:11]=[C:12]([S:14][CH3:15])[N:13]=2)=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:37]>C(Cl)Cl.CS(C)=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]3[CH2:18][CH2:17][N:16]([C@@:19]4([CH3:31])[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20]4)[C:10]=3[N:11]=[C:12]([S:14]([CH3:15])=[O:37])[N:13]=2)=[CH:4][N:3]=1
Reactant: CSc1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CS(=O)c1nc(-c2cnc(N)nc2)c2c(n1)N([C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a suspension of tert-butyl(3S)-3-[4-(2-aminopyrimidin-5-yl)-2-(methylsulfanyl)-5,6-dihydro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-3-methylpyrrolidine-1-carboxylate (352 mg, 0.794 mmol) in DCM (8 mL) was added m-chloroperoxybenzoic acid (254 mg, 1.03 mmol, 70% purity) in three portions over 1 min at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Four drops of DMSO was added and the reaction mixture was stirred for 5 min. The reaction mixture was purified via HPLC reversed phase column (XBridge C18 30×250 mm, mobile phase: 0%-50% of water with 0.1% EtOAc to acetonitrile with 0.1% EtOAc over 30 min, flow rate 80 mL/min) to give the title compound (200 mg, 55%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 2 H), 7.18 (s, 2 H), 3.89-3.75 (m, 2 H), 3.73-3.62 (m, 3 H), 3.42-3.34 (m, 3 H), 2.82 (s, 3 H), 2.41 (br s, 1 H), 2.15-2.01 (m, 1 H), 1.41 (s, 9 H), 1.33 (s, 3 H). m/z (APCI+) for C21H29N7O3S 460.6 (M+H)+.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:4]=1.[OH-:22].[Li+]>C1COCC1.O>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:4]=1)=[O:22]
Reactant: CCOC(=O)c1cc(C(Br)Br)nn1-c1ccc(OC)cc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C=O)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33 %

Procedure:
Ethyl 3-(dibromomethyl)-1-(4-methoxyphenyl)-1H-pyrazole-5-carboxylate (0.34 g, 0.813 mmol) was dissolved in 2 mL THF and lithium hydroxide (34 mg, 0.816 mmol) was dissolved in 0.5 mL water and added to the methanolic solution. After stirring at room temperature for 16 hours the solvent was evaporated, the residue was dissolved in 10 mL of water, acidified with 1N HCl and extracted with EtOAc to give 66 mg (33%) of the desired product after evaporation. 1H NMR (CDCl3): δ 10.06 (s, 1H); 7.56 (s, 1H); 7.40 (d, J=9.1, 2H); 7.01 (d, J=9.1, 2H); 4.54 (s, 2H); 3.88 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:19][Si](CC)(CC)CC)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:12])([F:13])[F:14])[C:15]([F:16])([F:17])[F:18])=[CH:8][CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 0.5 g (1.24 mmol) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine in 2 mL of DMF were added 0.3 mL (2.5 mmol) of benzylbromide and the mixture was stirred overnight at 80° C. After distribution between a 2M aqueous solution of NaOH and Et2O, drying of the combined organic phases over Na2SO4 and evaporation, the resulting crude was dissolved in 5 mL of MeOH, treated with 1 mL of a 2M NaOMe-solution in MeOH and stirred for 30 min. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 95: 5 gave 0.33 g (70%) of 2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow semisolid, MS: 378 (MH+).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl>[Zn].C1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:2]1([OH:10])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: O=C1Cc2ccccc2C1
Agent: Cl
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)Cc2ccccc2C1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of 2-indanone (13.2 g), ethyl bromoacetate (16.7 g), benzene (150 ml) and purified zinc (6.5 g) is stirred and heated at 50° C. Iodine (0.5 g) is added to catalyze the reaction. A rather vigorous reaction sets in after about 30 min. and the heating is discontinued. After the mixture ceases boiling, 4 g of fresh zinc and 10 g of ethyl bromoacetate is added, the reaction mixture is heated at reflux for 2 hr. and allowed to stand overnight at room temperature. The zinc addition-compound is decomposed by adding 200 ml of cold 10% hydrochloric acid. The aqueous layer is separated, extracted twice with benzene, all organic extracts are combined and dried (MgSO4). The filtrate is concentrated and the residue distilled under reduced pressure yielding 2-hydroxyindane-2-acetic acid ethyl ester, bp. 163°-166° C/10 mm.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCC1CC(F)(F)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC1CC(F)(F)C1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with (3,3-difluorocylobutyl)methanol (1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g, 8.6 mmol, 1.05 equiv) and CH2Cl2 (50 mL). The mixture was cooled to 0° C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was added via syringe. The mixture stirred for 12 h with warming to rt. After this time 1.0 M aq HCl (50 mL) was added. The layers were separated, the organic layer was extracted with CH2Cl2 (50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The compound was purified by flash chromatography on silica, eluting with 0-30% EtOAc in hexanes. This afforded (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) as an off white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N+:22]([O-])=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1.[OH-].[Na+].[H][H]>[Ni].O>[OH:1][C:2]1[C:7]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])=[CH:6][C:5]([C:13]([CH2:16][CH3:17])([CH3:15])[CH3:14])=[CH:4][C:3]=1[N:18]1[N:22]=[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]2=[N:19]1
Reactant: [H][H]
Reactant: CCC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)CC)c1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)CC)c1
Yield: 90.2 %

Procedure:
36.7 g (0.1 mol) of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole-N-oxide, 150 ml of water, 8 g (0.2 mol) of caustic soda and 5 g of Raney nickel were charged into a 500-ml stainless autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature of the resultant mixture was increased under agitation to 90° C. at which the mixture was then subjected to reaction for 8 hours until the absorption of hydrogen was stopped. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. The filtrate was then allowed to stand to separate an upper toluene layer. Most part of toluene layer was distilled off, and the resultant residual solid was crystallized from IPA and then dried to obtain 31.7 g of 2-(2'-hydroxy-3',5'-di-t-amylphenyl)benzotriazole (yield, 90.3%; melting point, 78° to 80° C.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:26]=[CH:25][C:8]([O:9][C:10]2[C:11]([N+:22]([O-:24])=[O:23])=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]3)=[C:7]([O:27][CH3:28])[CH:6]=1)([OH:3])=[O:2].[CH3:29][Si](Cl)(C)C>CO>[CH3:28][O:27][C:7]1[CH:6]=[C:5]([CH2:4][C:1]([O:3][CH3:29])=[O:2])[CH:26]=[CH:25][C:8]=1[O:9][C:10]1[C:11]([N+:22]([O-:24])=[O:23])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([C:19]([OH:21])=[O:20])=[CH:13]2
Reactant: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C(=O)O)cc2c1[N+](=O)[O-]
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C(=O)O)cc3c2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.4 (0.37 g, 0.96 mmol) in CH3OH (10 mL), was added TMSCl (0.1 g, 0.92 mmol). The mixture was stirred at room temperature for 3 h. Solvent was removed to give a residue, which was used without further purification. MS ESI (pos.) m/z: 401.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CS(=O)(=O)OCC1CCCC1
Reactant: Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(OCC2CCCC2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of 3-chloro-4-methylphenol (1.00 g) in N,N-dimethylformamide (8 ml) was added potassium carbonate powder (1.44 g) and the mixture was heated to 80° C. Thereto was added cyclopentylmethyl methanesulfonate (1.57 g) and the mixture was stirred at 120° C. for 3 hr. The reaction mixture was cooled to room temperature. Water was added and the mixture was extracted 3 times with hexane. The organic layers were combined and washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by column chromatography (silica gel, hexane) to give 2-chloro-4-((cyclopentyl)methyloxy)toluene (1.46 g) as a colorless oil.
Reaction SMILES: [N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:4]2=[CH:3][C:2]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27](O)=[O:28])=[CH:24][CH:23]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[S:26][C:25]([C:27]([N:9]2[CH2:8][CH2:7][CH2:6][N:5]3[N:1]=[C:2]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=[C:4]3[CH2:10]2)=[O:28])=[CH:24][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccccn2)s1
Reactant: CCOC(=O)c1cc2n(n1)CCCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)c1cc2n(n1)CCCN(C(=O)c1ccc(-c3ccccn3)s1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylate (0.033 g, 0.16 mmol) and 5-(2-pyridyl)thiophene-2-carboxylic acid (0.036 g, 0.18 mmol) in methylene chloride (1 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.07 g, 0.184 mmol) and N-methylmorpholine (0.053 mL, 0.48 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with methylene chloride (3 mL) and washed with saturated aqueous NaHCO3 (2 mL). The aqueous layer was extracted with additional methylene chloride (3 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness to afford Intermediate 31.