Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[C:4]=1[CH3:11])[CH3:2].[Cl:12][Si](C)(C)[CH3:14]>CO>[ClH:12].[CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([O:10][CH3:14])=[O:9])[C:4]=1[CH3:11])[CH3:2]
Reactant: C[Si](C)(C)Cl
Reactant: CCc1[nH]nc(C(=O)O)c1C
Solvent: CO
Product: CCc1[nH]nc(C(=O)OC)c1C
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a mechanically stirred suspension of 5-ethyl-4-methyl-1H-pyrazole-3-carboxylic acid (1.0 g, 6.49 mmol) in dry methanol (30 mL) was added chlorotrimethylsilane (2.5 mL, 19.5 mmol). The reaction mixture was heated at reflux over night. After being cooled to rt, the solvent was removed in vacuo, and the residue was stirred in diethyl ether (20 mL) for 1 h. After filtration and vacuum drying the title compound was obtained as white crystals (832 mg, 63%): 1H NMR (400 MHz, CDCl3) δ 10.55 (broad, 1H), 4.00 (s, 3H), 2.91 (quart, 2H), 2.32 (s, 3H), 1.35 (t, 3H); ES-MS m/z 169 (MH)+; HPLC RT (Method F) 1.52 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.S(Cl)(Cl)=O.[NH3:26]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([NH2:26])=[O:21])=[CH:5]2
Reactant: N
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: NC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reaction time: 2 h

Procedure:
To a suspension, stirred at 20° C., of 2 g (6.96 mmol) of 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared in step 1.1, in 80 mL of dry toluene are added 5.08 mL (69.62 mmol) of thionyl chloride. The reaction mixture is stirred for 2 hours at reflux and then concentrated under reduced pressure. The resulting product is taken up in 10 mL of dichloromethane and this solution is poured, dropwise, into a solution of 9.12 mL (69.62 mmol) of 30% aqueous ammonia in water. The reaction mixture is stirred for 14 hours at 20° C. After this time, a solid is collected by filtration and triturated in 50 mL of diisopropyl ether. After filtering and drying under reduced pressure, 0.58 g of expected product is collected.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1)#[CH:23]>CC#N.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][O:8][C:7]1[C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[N:3][CH:4]=[C:5]([O:20][CH3:21])[C:6]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: C#Cc1cnn(C)c1
Reactant: COc1ccc(COc2c(OC)cnc(I)c2OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a stirred solution of 2-iodo-3,5-dimethoxy-4-(4-methoxy-benzyloxy)-pyridine (95 mg, 0.237 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (30 mg, 0.283 mmol) in dry MeCN (1.5 ml) and NEt3 (0.5 ml) was added Pd(Ph3P)2Cl2 (12 mg, 7 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Copper (I) iodide (5 mg, 11 mol %) was added and the reaction mixture immediately became dark. Stirring was continued for 0.5 hours then the crude mixture was concentrated directly onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted sequentially with EtOAc:hexanes, 2:1, 3:1, 1:0) to give the product as a white solid (85 mg, 95%). 1H—NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.86 (d, J=2H), 5.13 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[O:24])[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH:21]4[CH2:23][O:22]4)=[CH:15][CH:14]=3)=[CH:9][O:10]2)=[CH:5][CH:4]=1.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(O)C>[CH:25]1([NH:31][CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([C:8]3[C:7](=[O:24])[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[O:10][CH:9]=3)=[CH:14][CH:15]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: COc1ccc2c(=O)c(-c3ccc(OCC4CO4)cc3)coc2c1
Solvent: CCO
Product: COc1ccc2c(=O)c(-c3ccc(OCC(O)CNC4CCCCC4)cc3)coc2c1
Yield: 66.1 %

Procedure:
A mixture of compound 3 (obtained from example 1) (0.32 g, 1 mmol), cyclohexylamine (0.50 g, 5 mmol), and ethanol (30 mL) was refluxed for 4 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:20) to give the title compound 5c (0.28 g, 67% yield). M.p.: 125-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23]([OH:25])=O)[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)[C:6]=1[CH3:37])=[O:4].[CH:38]([N:41]([CH:44]([CH3:46])C)[CH2:42]C)(C)C.CN(C(ON1N=NC2[CH:58]=[CH:59][CH:60]=[N:61][C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[CH:15][CH:16]=2)[N:9]2[C:19](=[O:26])[N:20]([CH2:22][C:23](=[O:25])[N:61]([CH2:60][CH2:59][CH2:58][CH2:46][CH2:44][N:41]([CH3:38])[CH3:42])[CH3:56])[N:21]=[C:8]2[N:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=2)[C:6]=1[CH3:37])=[O:4]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)O)c(=O)n2C1c1ccc(C#N)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)c2nn(CC(=O)N(C)CCCCCN(C)C)c(=O)n2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
Intermediate 17 (45 mg, 0.09 mmol) was dissolved in DMF (1 mL), and then diisopropylethylamine (75 μL, 0.44 mmol) and HATU (51 mg, 0.14 mmol) were added. The reaction mixture was stirred at RT for 30 minutes, then N,N,N-trimethylpentanediamine (63 mg, 0.44 mmol) was added, and stirring was continued for a further 18 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-10% (2M NH3 in MeOH) in DCM to give the title compound as a white solid (44 mg).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[O:30][CH:29]([CH3:31])[CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[CH3:31][CH:29]1[CH2:28][N:27]([C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:3]=2)[CH2:26][CH:25]([CH3:24])[O:30]1
Reactant: CC1CNCC(C)O1
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Solvent: CO
Product: CC1CN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC(C)O1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 2,6-dimethylmorpholine (35 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 35-65% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (41 mg, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19 (d, J=6.06 Hz, 6H) 1.46 (s, 6H) 2.68 (t, J=11.24 Hz, 2H) 3.80-3.91 (m, 2H) 4.38 (d, J=11.62 Hz, 2H) 6.37 (d, J=2.27 Hz, 1H) 7.40 (s, 1H) 7.60 (d, J=8.34 Hz, 2H) 8.00 (d, J=8.59 Hz, 2H) 8.10 (d, J=2.27 Hz, 1H) 10.91 (s, 1H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]=O.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([CH:17]=[O:18])[CH:14]=[CH:13][C:12]=1[OH:19]>C(O)C>[OH:19][C:12]1[C:13]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=1[O:10][CH3:9]
Reactant: C1COCCN1
Reactant: COc1cc(C=O)ccc1O
Reactant: C=O
Solvent: CCO
Product: COc1cc(C=O)cc(CN2CCOCC2)c1O

Procedure:
26.1 g (0.30 mol) of morpholine were added to 24.0 g (0.30 mol) of a 37% aqueous formaldehyde solution in 180 ml of ethanol. Then 30.4 g (0.20 mol) of 4-hydroxy-3-methoxybenzaldehyde (vanillin) were added. The reaction mixture was refluxed for one hour. After cooling the majority of the solvent was removed in a rotary evaporator. 250 ml of distilled water were added to the residue. After a certain time, a solid began to precipitate out, which was filtered out and dried.
Reaction SMILES: C(O[C@H]1[C@@H:31]2O[C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9](O)[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2(C)[C@H:11]3[CH2:12][CH2:13][C@@H:14]2C(C2OCC(C)(C)CO2)C)C1)(=O)C.N1C=CC=CC=1.[C:42]([O:45][C:46](=[O:48])[CH3:47])(=O)[CH3:43].[C:49]([O:52][CH2:53][CH3:54])(=O)C.CCCCCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:46]([O:45][C@H:42]1[CH2:31][CH2:30][C@@:29]2([CH3:33])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:14])[C@H:11]3[CH2:12][CH2:13][C@@H:54]2[CH:53]2[O:52][CH2:49]2)[CH2:43]1)(=[O:48])[CH3:47]
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Reactant: CCOC(C)=O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](C5CO5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
To a mixture of 49.0 mg (0.1 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate, 0.24 me (3 mmoles) of pyridine, 0.5 mg (0.004 mmole) of 4-(dimethylamino)pyridine and 10 ml of dry methylene chloride was added 0.12 ml (1.3 mmoles) of acetic anhydride dropwise at a temperature of 0° C. and the solution was stirred at room temperature for 10 hours. The reaction mixture was diluted with 20 ml of methylene chloride and washed with cold 1N-hydrochloric acid. The aqueous layer (washings) was extracted with methylene chloride and the extract was combined with the organic layer. The resulting mixture was washed successively with water, aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:10, v/v) to recover 45 mg of 7α-acetoxy-20 -(5,5-dimethyl-1,3-dioxan-2-yl)-1α, 260 -epoxypregn-5-en-3β-yl acetate (yield: 85%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.CC[O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([OH:25])=[O:23])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([CH:16]([CH3:18])[CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: CC(C)c1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1(4-chlorobenzyl)-1-(4-isopropylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting material, the title compound was prepared.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(=O)c1ccccc1
Product: O=C(C=Cc1ccc2ccccc2c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 2-naphthaldehyde and acetophenone, 3-(2-naphthalenyl)-1-phenylprop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1.[I:18]N1C(=O)CCC1=O>C1COCC1>[Cl:1][C:2]1[C:3]2[C:17]([I:18])=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2cc[nH]c2n1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)c[nH]c2n1
Yield: 80.6 %

Procedure:
A solution of N-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethyl-propionamide (101 g, 0.40 mol) in anhydrous THF (2 L) was treated with N-iodosuccinimide (98.9 g, 0.44 mol, 1.1 eq.) under N2 atmosphere at rt for 40 min. The solvent was evaporated, and the residue was taken up in CH2Cl2 (1.5 L), and washed with Na2SO3 (500 mL×3) and brine (300 mL×3). Evaporated and recrystallizion from MeOH gave the title product as a white powder (122 g, 81% yield, HPLC purity: 98.2%). tR: 6.19 min. 1H-NMR (DMSO-d6) δ 12.65 (br.s, 1H), 10.11 (br. s, 1H), 7.76 (d, 1H), 1.24 (s, 9H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.[NH2:18][C:19]([NH2:21])=[S:20]>CC(C)=O>[Br-:1].[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[CH:16]=[CH:17][C:3]([CH2:2][S:20][C:19]([NH2:21])=[NH2+:18])=[CH:4][CH:5]=2)=[O:8])=[CH:10][CH:11]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Solvent: CC(C)=O
Product: NC(=[NH2+])SCc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Product: [Br-]
Yield: 85.4 %

Procedure:
An acetone solution (500 ml) of 4-bromomethyl-4'-chlorobenzophenone (31 g) and thiourea (10 g) was heated for 30 minutes with refluxing. The precipitated crystals were then collected by filtration and washed with acetone to obtain S-(4-(4-chlorobenzoyl)benzyl)thiouronium bromide (33 g).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]1[CH:59]=[CH:58][N:57]=[C:56]1[CH2:60][CH2:61]O>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:61][CH2:60][C:56]4[N:55]([CH3:54])[CH:59]=[CH:58][N:57]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: Cn1ccnc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCc1nccn1C
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
Diethyl azodicarboxylate (128 μl, 1.5 mmol) was added dropwise to a solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (410 mg, 1.5 mmol) and 2-(1-methylimidazol-2-yl)ethanol (147 mg, 1.15 mmol), (EP 0675112 A1), in methylene chloride (4 ml) and the mixture was stirred for 30 minutes at ambient temperature. Further triphenylphosphine (143 mg, 0.52 mmol) and diethyl azodicarboxylate (85 μl, 1 mmol) were added and the mixture stirred for 1 hour at ambient temperature. The solid product was collected by filtration and washed with methylene chloride. The solid was dissolved in a mixture of methylene chloride (25 ml) and methanol (25 ml), and a solution of 2.9M ethereal hydrogen chloride (2 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-yl)ethoxy)quinazoline hydrochloride (133 mg, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC=CC=1.[Li]CCCC.[C:32](=[O:34])=[O:33]>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])=[C:5]([C:6]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:8]=1)[C:32]([OH:34])=[O:33]
Reactant: O=C=O
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C(F)(F)F)c(C(=O)O)c1NC(=O)C(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
N-(2-methoxy-5-(trifluoromethyl)phenyl) pivalamide (1 eq) was azeotrope with toluene (x=3). Dissolved in THF, cooled to −50° C. and added n-BuLi (2 eq, 2.5M solution in hexane) dropwise. The reaction mixture was stirred at −50° C. for 1 h then warmed to −10° C. in 30 min. Stirred at this temperature for 30 min then CO2 gas was passed through cylinder into the reaction mixture at −10 to 0° C. for 1 h. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was poured to water and extracted with ethyl acetate. (EtOAc extracts contained starting material). The aq layer pH was adjusted to 1-2 and product was extracted with ethyl acetate (x=3). The ethyl acetate extracts were combined, washed with brine and dried over sodium sulfate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][OH:9])[CH:7]=1.[H-].[Na+].[CH3:13]I.O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:8][O:9][CH3:13])[CH:7]=1
Reactant: OCc1cc(Br)ccc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (5-bromo-2-fluorophenyl)methanol (5.00 g) in THF (100 ml) was added 60% sodium hydride (1.08 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (3.80 ml) was added, and the mixture was stirred for 1.5 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried. The solvent was evaporated under reduced pressure and the residue was purified by column chomatography (eluent, hexane→hexane:ethyl acetate=50:1) to give the title compound (4.86 g) as a brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2].O[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][O:21][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)COc1ccc(Sc2ccc(CO)cc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Sc2ccc(COc3ccc(C(F)(F)F)cc3)cc2)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
An oven-dried 500 mL round-bottomed flask was charged with crude 7.3 (prepared from 7.2 (30.0 g, 90.2 mmol)) and DMF (200 mL) and cooled to 0° C. Next, 4-hydroxybenzotrifluoride (17.5 g, 108 mmol) and K2CO3 (24.9 g, 180 mmol) were added at 0° C., and the reaction heated to 70-80° C. and stirred for 2 h. The reaction mixture was poured into ice-water (400 mL), and the product was extracted with toluene (400 mL). The organic layer was successively washed with water (2×300 mL) and brine (400 mL), dried over MgSO4, and concentrated to give a slightly yellow oil which was purified by flash chromatography (SiO2 gel 60 N, eluted with AcOEt/hexane=⅙). The fractions containing only desired product were combined and concentrated to a slightly yellow oil (40.9 g). 1H NMR (400 MHz) (CDCl3) δ 7.53 (2H, d, J=8.6 Hz); 7.30-7.20 (4H, m); 7.17 (2H, d, J=8.4 Hz); 7.00 (2H, d, J=8.7 Hz); 6.68 (1H, d, J=8.4 Hz); 5.04 (2H, s); 4.66 (2H, s); 4.27 (2H, q, J=7.1 Hz); 2.27 (3H, s); 1.30 (3H, t, J=7.1 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)NCC2
Yield: 122.2 %

Procedure:
A solution of 6-nitroindoline (1 g, 6.1 mmol) in 50 mL of ethyl acetate was hydrogenated under an atmosphere of hydrogen with Pd-C 10% (100 mg) at rt for 3 h. Filtration over celite afforded 1.0 g (98%) of 6-aminoindoline. Data for 6-aminoindoline: 1N NMR (400 MHz, CDCl3) 7.40 (d, J=7.4, 1H), 6.05 (d, J=2.0, 1H), 6.03 (d, J=7.5, 1H), 3.67 (bs, 1H), 3.49 (t, J=8.1, 2H), 3.48 (bs, 2H), 2.90 (t, J=8.2, 2H).
Reaction SMILES: [NH2:1][C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[C:3]([C:6]#[N:7])[C:4]#[N:5].[SH2:12].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]([O:8][CH:9]([CH3:11])[CH3:10])=[C:3]([C:4]#[N:5])[C:6](=[S:12])[NH2:7]
Reactant: CC(C)OC(N)=C(C#N)C#N
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)OC(N)=C(C#N)C(N)=S

Procedure:
In the manner of Example V, part B, 117.6 g of 3-amino-2-cyano-3-isopropoxy-2-propenenitrile were allowed to react with excess hydrogen sulfide gas in a solution of 157.4 g of triethylamine and 250 ml of pyridine. The volatile materials were removed under reduced pressure and water was added to the residue. The yellow precipitate was collected and dried. The dried solid was recrystallized from isopropanol to yield 123 g of 3-amino-2-cyano-3-isopropoxy-2-propenethioamide, mp 170° (decomposes). The ir and nmr spectra were consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH2:19][OH:20])[C:3]=1[O:23][CH3:24].C[N+]1([O-])CCOCC1.ClCCl>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:17](/[CH3:22])=[C:18](/[F:21])\[CH:19]=[O:20])[C:3]=1[O:23][CH3:24]
Reactant: COc1c(/C(C)=C(/F)CO)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: COc1c(/C(C)=C(/F)C=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C

Procedure:
As described in General Procedure H-1, (2E)-3-(4-bromo-8-isopropyl-3-methoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-en-1-ol (Compound A-135, 130 mg, 0.33 mmol), tetrapropylammonium perruthenate (10 mg, 0.028 mmol) and 4 methylmorpholine N-oxide (77 mg, 0.66 mmol) were reacted in acetonitrile and dichloromethane to give the title compound after purification by flash column chromatography (silica gel, 5% ethyl acetate in hexane).