Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC1C=CC=C([N+]([O-])=O)C=1)(C(OCC)=O)C(OCC)=O.CO[C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][C:34]=1[CH2:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([N+:45]([O-])=O)[CH:43]=2)[CH:38]=[N:37]1)[C:28]([O:30][CH3:31])=[O:29]>>[NH2:45][C:42]1[CH:43]=[C:44]2[C:39]([CH:38]=[N:37][N:36]2[CH2:35][C:34]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:40][CH:41]=1
Reactant: COC(=O)c1ccc(Cn2ncc3ccc([N+](=O)[O-])cc32)c(OC)c1
Agent: CCOC(=O)C(C)(Oc1cccc([N+](=O)[O-])c1)C(=O)OCC
Product: COC(=O)c1ccc(Cn2ncc3ccc(N)cc32)cc1

Procedure:
In like manner to the reduction of diethyl 2-methyl-2-(3-nitrophenoxy)malonate, methyl 3-methoxy-4-[(6-nitroindazol-1-yl)methyl]benzoate was reduced to provide methyl 4-[(6-aminoindazol-1-yl)methyl]benzoate. 1H NMR (CDCl3): δ 7.88 (s, 1H), 7.53 (d, 1H, J=8.8 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.50 (d, 1H, J=1.7 Hz), 6.67 (d, 1H, J=8.8 Hz), 6.56 (dd, 1H, J=1.7 and 8.8 Hz), 6.45 (d, 1H, J=1.2 Hz), 5.50 (s, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.79 (br s, 2H).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8]N)[CH2:4][O:3]1.FC1C(NC2C=CC(I)=CC=2F)=C(C=CC=1F)C(O)=O.O[C@H](CO)CO[NH:35][C:36](=[O:54])[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[C:39]([F:44])[C:38]=1[NH:45][C:46]1[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=1[F:53]>CO>[OH:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3][C:41]1[C:40]([F:43])=[C:39]([F:44])[C:38]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([I:52])=[CH:48][C:47]=2[F:53])=[C:37]([CH:42]=1)[C:36]([NH2:35])=[O:54]
Reactant: O=C(NOC[C@H](O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CC1(C)OC[C@@H](CON)O1
Agent: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Solvent: CO
Product: NC(=O)c1cc(OC[C@@H](O)CO)c(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
Prepared from (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine and 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid by the procedure described above for N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide: m.p. 116-118° C. (Form II of Compound C); and m.p. 116-118° C. (Form I of Compound C); [α]=+1.77° (c=1.13, methanol). Analysis: Calcd. For: C16H14F3I1N2O4: C, 39.85; H, 2.93; N, 5.81; F, 11.82, I, 26.32. Found: C, 40.01; H, 2.73; N, 5.84; F, 11.45; I, 26.42.
Reaction SMILES: C([C:3]1(CC)[C@H:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)[N:5](C(N[C@H](CCC)C2C=CC(C)=CC=2)=O)[C:4]1=[O:30])C.[P:33]([O:40]CC)([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].C(OCC)(=O)C>CCCCCC>[CH2:35]([O:34][P:33]([CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH:6]2[NH:5][C:4](=[O:30])[CH2:3]2)=[CH:13][CH:12]=1)([O:37][CH2:38][CH3:39])=[O:40])[CH3:36]
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(CBr)cc1)c1ccc(C)cc1
Reactant: CCOP(OCC)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(OC2CC(=O)N2)cc1)OCC
Temperature: 90 °C

Procedure:
A mixture of (4S)-3,3-diethyl-1-[(R)-α-n-propyl-(4-methyl)-benzylaminocarbonyl]-4-[4-(bromomethyl)phenoxy]-azetidin-2-one (362 mg, 0.72 mmol) and triethyl phosphite (1.4 mL, 8.2 mmol) was heated for 2 hours at 90° C. The crude product mixture was subjected to flash chromatography on silica gel using initially 25% ethyl acetate in hexane and subsequently 33% ethyl acetate in hexane as the mobile phase. (4S)-3,3-Diethyl-1-[(R)-α-n-propyl(4-methyl)-benzylaminocarbonyl)]-4-[4-(diethoxyphosphinylmethyl)-phenoxy]-azetidin-2-one was obtained as colorless oil; yield 371 mg, 92%; Fast atom bombardment mass spectrum (FAB MS): m/z 559 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[C:34]([CH3:36])[N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH2:37]([O:39][C:40](=[O:46])[C:41](=[N+]=[N-])[CH2:42][CH3:43])[CH3:38].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH:41]([CH2:42][CH3:43])[C:40]([O:39][CH2:37][CH3:38])=[O:46])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[C:34]([CH3:36])[N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2nc(C)nn12
Reactant: CCOC(=O)C(CC)=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2nc(C)nn12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.77 g), rhodium(II) acetate (dimer) (0.0070 g) and toluene (10 mL) was heated to 80° C. under an argon atmosphere, a solution of 2-diazobutyric acid ethyl ester (0.91 g) in toluene (10 mL) was added dropwise, and the mixture was stirred at 80° C. for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.69 g, 73%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.Br[CH2:23][C:24]1[C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[C:28]([O:37]C(OC(C)(C)C)=O)[C:27]([C:45]([F:48])([F:47])[F:46])=[CH:26][CH:25]=1>>[C:3]([O:32][C:30]([C:29]1[C:28]([OH:37])=[C:27]([C:45]([F:46])([F:48])[F:47])[CH:26]=[CH:25][C:24]=1[CH2:23][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:3]2[CH:4]=[CH:5][C:6]([CH:9]([CH3:14])[C:10]([OH:12])=[O:11])=[C:7]([F:8])[C:2]=2[F:1])=[CH:16][CH:17]=1)=[O:31])([CH3:15])([CH3:4])[CH3:2]
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(F)c1F
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CC(C(=O)O)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c(F)c1F

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from methyl 2-(2,3-difluoro-4′-hydroxy-1,1′-biphenyl-4-yl)propanoate (193 mg, 0.661 mmol) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (306 mg, 0.726 mmol) obtained in Example (28-5), the title compound was obtained as a white powder (45 mg, yield: 12%).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2-].[Li+].[Cl:12][C:13]1[N:14]=[N:15][C:16](Cl)=[CH:17][CH:18]=1>O1CCCC1>[C:1]1([CH:7]([C:16]2[N:15]=[N:14][C:13]([Cl:12])=[CH:18][CH:17]=2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: N#CCc1ccccc1
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: N#CC(c1ccccc1)c1ccc(Cl)nn1
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a solution of 8.2 g (0.07 mole) of phenylacetonitrile in 50 ml of dry tetrahydrofuran was added 1.61 g (0.07 mole) of pulverized lithium amide. The mixture was refluxed for 5 hours. To the reaction mixture thereafter cooled were added 8.2 g (0.055 mole) of 3,6-dichloropyridazine and 10 ml of tetrahydrofuran on a water-ice bath. The mixture was then allowed to stand overnight at room temperature. The resulting mixture was neutralized and then distilled to remove the tetrahydrofuran. The residue was chromatographed over silica gel, followed by recrystallization from a mixture of ethanol and isopropyl ether, giving 5.4 g (42.9% yield) of 2-phenyl-2-(6-chloro-3-pyridazinyl)acetonitrile in the form of pale red needles, m.p. 131° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:5]=[C:6]([CH3:20])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]=2[N:9]=1)[CH3:2].C(O)(=O)C.[Br:25]Br>C(Cl)Cl.O>[Br:25][C:12]1[C:11](=[O:14])[N:10]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:8]2[N:9]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[C:6]([CH3:20])[C:7]=2[CH:13]=1
Reactant: CCNc1nc(C)c2ccc(=O)n(CCCOC)c2n1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CCNc1nc(C)c2cc(Br)c(=O)n(CCCOC)c2n1
Reaction time: 0.08 h
Yield: 56.3 %

Procedure:
To a solution of 2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (0.18 g, 0.65 mmol), acetic acid (5 mL) and dichloromethane (3 mL) was added bromine (36 ul, 0.7 mmol). The mixture was stirred for 5 minutes, and then diluted with DCM and water. The organic layer was washed with sat. sodium bicarbonate (3 times), brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography to gave 0.13 g (56% yield) of 6-bromo-2-(ethylamino)-8-(3-methoxypropyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one. 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 5.44 (Br. s, 1H), 4.55 (m, 2H), 3.54-3.47 (m, 4H), 3.33 (s, 3H), 2.53 (s, 3H), 2.05-2.00 (m, 2H), 1.30-1.23 (m, 3H); MS (EI) for C14H19BrN4O2: 355 (MH+).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([NH2:11])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1)[CH:2]=[CH2:3].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=[O:19]>CN1C(=O)CCC1.O>[CH2:1]([NH:4][C:5]1[C:10]([NH:11][C:18]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)=[O:19])=[C:9]([Cl:12])[N:8]=[CH:7][N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1ncnc(Cl)c1N
Reactant: O=C(Cl)c1cccs1
Solvent: CN1CCCC1=O
Solvent: O
Product: C=CCNc1ncnc(Cl)c1NC(=O)c1cccs1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
N*4*-Allyl-6-chloro-pyrimidine-4,5-diamine (0.20 g, 0.0011 mol) was taken in NMP (3 ml). Thiophene-2-carbonyl chloride (0.14 ml, 0.0013 mol) was added slowly at 0° C. and stirred for 2 hrs at same temperature. The reaction mixture was diluted with water (10 ml) and extracted with DCM (3×5 ml). The organic layer was washed with saturated NaHCO3 solution (10 ml), followed by brine (10 ml) and dried over Na2SO4. The solvent was removed to get thiophene-2-carboxylic acid (4-allylamino-6-chloro-pyrimidin-5-yl)-amide (0.281 g, 88%) as a pale yellow solid.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]1=2.[CH2:20]([S:22]([NH:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:24])=[O:23])[CH3:21]>>[CH3:15][O:14][C:12]1[CH:11]=[CH:10][C:9]2[C:3](=[CH:2][C:28]3[CH:27]=[C:26]([NH:25][S:22]([CH2:20][CH3:21])(=[O:24])=[O:23])[CH:31]=[CH:30][CH:29]=3)[C:4]3[CH:19]=[CH:18][CH:17]=[CH:16][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:13]=1
Reactant: COc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Product: CCS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3cc(OC)ccc32)c1

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-2-methoxy-10,11dihydro-5H-dibenzo[a,d]cycloheptene (E/Z mixture, 97 mg, 0.31 mmol) with 3-ethanesulfonylaminophenylboronic acid (78 mg, 0.34 mmol) to give 57 mg (44%) of an E/Z mixture of the title compound. MS (ES) 420 (M+1) weak, 418 (M−1). HPLC shows 45% of the E isomer and 53% of the Z isomer.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH3:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:39][NH:40]2)C1C=CC=CC=1)C>>[CH3:22][C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:40][CH3:39])=[O:3])[CH:14]=2)[NH:18][N:17]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(C)c2c1
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(C)c2c1

Procedure:
3-(3-Methyl-1H-indazol-5-yl)-N-methyl 3-phenyl-acrylamide CCXX was prepared from 3-(3-methyl-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[NH:7][N:6]=[CH:5]2.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.N1C=CC=CC=1>C(Cl)Cl.C(O[Cu]OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[N:7]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[N:6]=[CH:5]2
Reactant: Cc1cc2[nH]ncc2cc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1Br
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of 5-bromo-6-methyl-1H-indazole (2.89 g, 13.69 mmol,) in DCM (137 mL) was added 4-fluorophenylboronic acid (3.83 g, 27.4 mmol), diacetoxycopper (2.48 g, 13.7 mmol), pyridine (2.2 mL, 27.4 mmol) and 4 Å molecular sieves. The reaction was stirred open to air for about 4 h. The reaction mixture was filtered through a pad of Celite® rinsing with EtOAc (80 mL) and then concentrated to about (60 mL) under reduced pressure. Water was added (40 mL) and the layers were separated. The aqueous layer was back extracted with EtOAc (20 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, EtOAc/heptane 100:0 to 0:20) to afford 5-bromo-1-(4-fluorophenyl)-6-methyl-1H-indazole (2.68 g, 8.78 mmol, 64%). LC-MS (Table 1, Method g) Rt=2.75 min, m/z 305, 307 (M+H)+. 1H NMR (CDCl3) δ 8.07 (s, 1H), 7.98 (s, 1H), 7.69-7.59 (m, 2H), 7.52 (s, 1H), 7.28-7.18 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)=[O:4].S(Cl)(Cl)=O.[CH2:18]([N:25]1[CH:29]=[CH:28][N:27]=[CH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(#N)C>[CH2:18]([N:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:8]([C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(Cn2ccnc2)cc1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cccc(C(=O)c2nccn2Cc2ccccc2)c1
Yield: 85.2 %

Procedure:
A solution of 3-(methoxycarbonyl)benzoic acid (2.53 g, 14.0 mmol) in thionyl chloride (7.17 ml, 98.30 mmol) was heated at reflux for 1 h. The mixture was cooled and concentrated in vacuo and to the residue was added toluene. This solution was concentrated in vacuo and to the residue was added anhydrous acetonitrile (24 ml), 1-benzyl-1H-imidazole (2.22 g, 14.0 mmol) and triethylamine (2.35 ml, 16.9 mmol). The reaction mixture was heated at reflux for 18 h and then cooled and concentrated in vacuo. To the residue was added ethyl acetate and the solution was washed with water and saturated aqueous sodium hydrogen carbonate solution. The organic phase was filtered through silica, eluting with ethyl acetate, and the filtrate was concentrated in vacuo to give the title compound (3.82 g).
Reaction SMILES: [F:1][CH:2]([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[N+:12]([O-])([OH:14])=[O:13]>ClCCCl>[F:1][CH:2]([F:11])[O:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1ccc(OC(F)F)cc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1cc(OC(F)F)ccc1O
Temperature: 0 °C
Yield: 85.9 %

Procedure:
4-(Difluoromethoxy)phenol (500 mg, 3.12 mmol) was dissolved in DCE (3 mL). The reaction mixture was cooled to 0° C. and nitric acid (0.488 mL, 10.92 mmol) was added dropwise over 10 min. The reaction mixture was stirred for a further hour at 0° C., then poured into an ice/water mix (5 g in 5 mL). DCE (10 mL) was added and the layers separated. The organic layer was dried (MgSO4) and evaporated to dryness to give a crude brown oil (550 mg). Material was carried forward without further purification, as no separation between products was found in TLC solvent systems used.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[O:16][C:15](=[O:17])[NH:14][C@H:13]2[C:18](OC)=[O:19])=[CH:8][CH:7]=1.[BH4-].[Na+].Cl>CCO>[OH:19][CH2:18][C@H:13]1[C@H:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=2)[O:16][C:15](=[O:17])[NH:14]1
Reactant: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2C(=O)OC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a suspension of (4R,5S)-methyl 5-(4-(2-methoxyethoxy)phenyl)-2-oxooxazolidine-4-carboxylate (2.30 g, 7.79 mmol) in EtOH (45 mL) was added in portions at 0-5° C. sodium borohydride (648 mg, 17.1 mmol). The reaction mixture was stirred for 0.5 h at RT and then acidified with 4M aqueous HCl (10 mL) at 0-5° C. The reaction mixture was concentrated and the product was extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound as a beige foam (1.80 g, 81%). tR=0.498 min (UPLC 1); LC-MS: [M+H] 268; Rt 0.55 min; (LCMS method 2); 1H NMR (400 MHz, CDCl3): 7.31 (d, 2H), 6.96 (d, 2H), 6.45 (br s, 1H), 5.33 (d, 1H), 5.30 (br s, 1H), 3.75-4.30 (m, 7H), 3.47 (s, 3H).
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[N:17]=[C:16]([CH3:18])[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1.[CH2:25]([NH:32][C:33]([C:35]1[S:39][C:38]([N:40]2[CH2:44][CH2:43][NH:42][C:41]2=[O:45])=[N:37][C:36]=1[CH3:46])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][C:33]([C:35]1[S:39][C:38]([N:40]2[CH2:44][CH2:43][N:42]([CH2:12][C:13]3[N:17]=[C:16]([CH3:18])[N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=3)[C:41]2=[O:45])=[N:37][C:36]=1[CH3:46])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1nc(CBr)nn1-c1ccccc1
Agent: N#Cc1ccc(CCl)cc1
Product: Cc1nc(N2CCN(Cc3nc(C)n(-c4ccccc4)n3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 17 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with 3-(bromomethyl)-5-methyl-1-phenyl-1H-1,2,4-triazole to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 17% yield: mp 139-141° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.98 (d, J=8.3 Hz, 2H), 7.49-7.29 (m, 8H), 5.88 (s, 1H), 4.62 (s, 2H), 4.57 (d, J=5.6 Hz, 2H), 4.13-4.08 (m, 2H), 3.68-3.62 (m, 2H), 2.63 (s, 3H), 2.41 (s, 3H); MS (ES+) m/z 488.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:24][C:25]([F:28])([F:27])[F:26])(=O)=O.O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[O:11])[CH3:10])=[N:4][CH:5]=[C:6]([O:8][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:7]=1
Reactant: CC(=O)c1ncc(O)cc1Cl
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ncc(OCC(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To 1.0 g of 1-(3-chloro-5-hydroxypyridin-2-yl)ethanone in 15 ml of N,N-dimethylformamide, 1.2 g of potassium carbonate and 1.6 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 40 ml of water and extracted with ethyl acetate (50 ml×1), the resulting organic layer was washed with water (20 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 1.2 g of the desired product as white crystals.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([O:8]C)[CH:5]=[CH:6][CH:7]=1.Br[CH:11]([CH3:21])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=O>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:7]3[CH:6]=[CH:5][C:4]([OH:8])=[CH:3][C:2]=3[S:1][C:11]=2[CH3:21])=[CH:15][CH:16]=1
Reactant: COc1cccc(S)c1
Reactant: CC(Br)C(=O)c1ccc(Br)cc1
Product: Cc1sc2cc(O)ccc2c1-c1ccc(Br)cc1

Procedure:
In analogy to examples 26.1-26.3, 3-mercaptoanisole and 2,4′-dibromopropiophenone were converted to yield 3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophen-6-ol as colorless amorphous solid, MS: 318 (M, 1Br).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:19][NH:20][CH3:21]>O1CCCC1>[CH3:19][N:20]([CH2:2][C:3]1[N:4]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:21]
Reactant: CNC
Reactant: CCOC(=O)c1sc(-c2ccccc2)nc1CBr
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(-c2ccccc2)nc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The compound prepared in Example 126 (1.00 g) was suspended in tetrahydrofuran (20 mL) and dimethylamine (2 M) (7.66 mL) added and the reaction mixture stirred at room temperature for 3 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried, magnesium sulfate and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography to afford the title compound (0.65 g) having the following physical data.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[CH:11]1([NH2:14])[CH2:13][CH2:12]1>>[CH:11]1([NH:14][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=2)=[O:10])[CH2:13][CH2:12]1
Reactant: O=C(O)c1cccc(Br)n1
Reactant: NC1CC1
Product: O=C(NC1CC1)c1cccc(Br)n1

Procedure:
Prepared according to the procedure described in Example 121, Step 1, using 6-bromo-pyridine-2-carboxylic acid and cyclopropylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[C:13]([O:16][C:17]1[C:18]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:19][C:20]2[O:24][C:23]([CH2:26]I)([CH3:25])[CH2:22][C:21]=2[C:28]=1[C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:15])[CH3:14].[Cl-].[NH4+]>CN(C)C=O>[C:13]([O:16][C:17]1[C:18]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:19][C:20]2[O:24][C:23]([CH3:25])([CH2:26][O:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:22][C:21]=2[C:28]=1[C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 3.76 g of 4-nitrophenol in 25 ml of N,N-dimethylformamide was added dropwise to an ice-cooled suspension of 1.08 g of 60% oily sodium hydride in 50 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Then, the reaction solution was cooled to 0° C. and a solution of 10 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 70-2) in 25 ml of N,N-dimethylformamide was added dropwise, and the mixture was heated under reflux for 14 hours. After cooling, the reaction solution was combined with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography eluting with n-hexane containing 20% ethyl acetate to give 6.57 g of 5-acetoxy-4,6-di-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2,3-dihydrobenzofuran (rotamer mixture) as a pale yellow oil (yield 64%).