Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[N:18][C:19]=3[NH2:21])[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][NH:24]3)[N:13]=2)=[CH:8][CH:7]=1.[C:31]([CH2:33][C:34](O)=[O:35])#[N:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH2:22][C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:34](=[O:35])[CH2:33][C:31]#[N:32])[N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][C:4]4[CH:28]=[CH:29][CH:30]=[C:2]([F:1])[CH:3]=4)=[CH:7][CH:8]=3)[C:20]=12
Reactant: N#CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3)cc1)nn2C[C@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Into a 100-mL round-bottom flask, was placed 3-[4-(3-fluorophenoxy)phenyl]-1-[(2R)-pyrrolidin-2-ylmethyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (216 mg, 0.53 mmol, 1.00 equiv), 2-cyanoacetic acid (36.8 mg, 0.43 mmol, 0.80 equiv), HATU (166 mg, 0.44 mmol, 0.80 equiv), triethylamine (109 mg, 1.08 mmol, 2.00 equiv), N,N-dimethylformamide (50 mL). The resulting solution was stirred for 3 h at 25° C. The resulting solution was extracted with ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was loaded on a silica gel column and eluted with dichloromethane methanol (50 l) to give 150 mg (60%) of 3-[(2R)-2-([4-amino-3-[4-(3-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl)pyrrolidin-1-yl]-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].[CH3:73]I>C(OCC)(=O)C.[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:53][CH3:73])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Reactant: CI
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OC)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-phenyl-2'"-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (27 mg) in methyl iodide (0.5 ml) under nitrogen atmosphere was added silver oxide and the reaction was stirred at room temperature for 48 hours. The reaction was then diluted with ethyl acetate and filtered through a silica gel pad. The filtrate was concentrated and purified by column chromatography on silica gel eluting with 60% hexane:40% ethyl acetate to give the desired compound (12.6 mg).
Reaction SMILES: [Mg].II.Br[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[O:10]([C:17]1[CH:18]=[C:19]([N:23]2[CH:27]=[CH:26][CH:25]=[C:24]2[CH:28]=[O:29])[CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[Cl-]>CCOCC>[OH:29][CH:28]([C:24]1[N:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:18]=2)[CH:27]=[CH:26][CH:25]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCBr
Reactant: O=Cc1cccn1-c1cccc(Oc2ccccc2)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCCCCC(O)c1cccn1-c1cccc(Oc2ccccc2)c1
Reaction time: 0.75 h
Yield: 17.3 %

Procedure:
Magnesium turnings (2.4 g, 100 mmol) were activated with a crystal of iodine by heating under nitrogen the cooled magnesium and 6.1 g of 1-bromopentane (40 mmol, 99% purity) in 200 mL of ether. The reaction medium was heated to reflux and the reaction was self-sustaining. After 0.75 h the reaction was complete and the mixture was cooled to ice bath temperatures and 5 g of 1-(3-phenoxyphenyl)-pyrrole-2-aldehyde (19 mmol) in 25 mL of ether was added. The reaction was stirred for 1 h and poured into 500 ml of 1N NH4Cl solution. The product was extracted into ether and the ether was cross washed with 1 N NH4Cl solution. The etherate was separated, dried with MgSO4 and filtered, and the solvent was evaporated, yielding 6.35 g of crude product. The product was column chromatographed three times on silica gel (for dry column chromatography) and finally on Florisil eluting with ether acetate/hexane (1:40, v/v). After solvent removal, there was obtained 1.1 g of the final product. The product gave correct elemental analysis and spectral identification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Br:14])[CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[CH:10]2)=[O:4].Cl>[OH-].[Na+].C(O)C>[Br:14][C:7]1[CH:8]=[C:9]2[C:13](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:12][CH:11]=[CH:10]2
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(Br)cc2cc[nH]c12
Temperature: 40 °C
Reaction time: 2 h

Procedure:
409 mg of 5-bromo-1H-indole-7-carboxylic acid methyl ester (1.61 mmol) were suspended in a mixture of 1.6 ml 2N NaOH and 1.6 ml ethanol and stirred at 40° C. for 2 h. After cooling down, the mixture was treated with 2N aqueous HCl, and extracted twice with EtOAc. The organic phase was the washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 353 mg of 5-bromo-1H-indole-7-carboxylic acid as a light brown solid (85%). MS (ISP) 237.9 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:16]1[O:18][C@@H:17]1[CH2:19]Cl>>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C@H:17]2[CH2:16][O:18]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: ClC[C@@H]1CO1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(OC[C@H]2CO2)cc1

Procedure:
The title compound was prepared from 4-(1,1,3,3-tetramethyl-butyl)-phenol and S-epichlorohydrin employing the procedures as set forth in Step 1 of Example 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:12]([F:21])[CH:11]=1.C(=O)([O-])O.[Na+].C1(C)C=CC=CC=1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:21][C:12]1[CH:11]=[C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OB(O)c1cccs1
Reactant: CCCCCc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2cccs2)cc1F
Temperature: 80 °C

Procedure:
A mixture of 40.0 g (0.31 mol) of thiophen-2-ylboronic acid, 80.0 g (0.32 mol) of 4-bromo-2-fluoro-1-pentylbenzene, 18.0 g (15.6 mmol) of tetrakis(triphenylphosphine)palladium(0) and 400 ml of 2 M sodium hydrogencarbonate solution in 1000 ml of ethanol/toluene=3:2 is heated at 80° C. for 19 h. Toluene and water are added to the mixture, and the organic phase is separated off. The aqueous phase is extracted with toluene, and the combined organic phases are washed with sat. sodium chloride solution. The solution is dried using sodium sulfate and evaporated to dryness. The residue is purified by column chromatography (SiO2, n-heptane). 2-(3-Fluoro-4-pentylphenyl)thiophene is obtained as a colourless liquid.
Reaction SMILES: Cl.[Br:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][NH2:13])[C:6]=2[S:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1>C(O)C>[Br:2][C:3]1[C:7]2[N:8]=[CH:9][N:10]=[C:11]([NH:12][N:13]=[CH:20][C:16]3[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=3)[C:6]=2[S:5][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: NNc1ncnc2c(Br)csc12
Agent: Cl
Solvent: CCO
Product: Brc1csc2c(NN=Cc3cccnc3)ncnc12
Temperature: 25 °C
Yield: 79.8 %

Procedure:
A suspension of (7-bromothieno[3,2-d]pyrimidin-4-yl)hydrazine hydrochloride (168, 29 mg, 0.12 mmol) and 3-pyridinecarboxaldehyde(18 mg, 0.17 mmol) in ethanol (2 mL) was heated at reflux for 4 hours. After cooling to room temperature, the solid product was collected by vacuum filtration to yield 3-pyridinecarboxaldehyde(7-bromothieno[3,2-d]pyrimidin-4-yl)hydrazone (32 mg, 81% yield) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[N:19]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[Li+].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:7]1[O:6][C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][S:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:31][CH:30]=1)(=[O:33])=[O:34]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: O=S([O-])c1ccc(CN2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(CN4CCCCC4)cc3)c(C)o2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
A mixture of methyl 4-(4-(chloromethyl)-5-methyloxazol-2-yl)benzoate (2.65 g, 10.00 mmol, 1.00 equiv), lithium 4-(piperidin-1-ylmethyl)benzenesulfinate (4.8 g, 19.59 mmol, 2.00 equiv) and potassium carbonate (1.38 g, 10.00 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL) was stirred overnight at 70° C. Water (150 mL) was added and the resulting solution was extracted with 3×200 mL of ethyl acetate. The combined organic layers was washed with 3×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to yield 4 g (53%) of methyl 4-(5-methyl-4-((4-(piperidin-1-ylmethyl)phenylsulfonyl)methyl)oxazol-2-yl)benzoate as a yellow solid. LC-MS: (ES, m/z): 510 [M+CH3CN+H]+, 469 [M+H]+, 120.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11]I)=[CH:8][O:9][C:5]=2[CH:4]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH:25]=1)[N:22]=[CH:21][CH:20]=[CH:19]2>>[CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[C:7]([CH2:10][CH2:11][N:29]3[CH2:30][CH2:31][N:26]([C:24]4[CH:25]=[C:16]([Cl:15])[CH:17]=[C:18]5[C:23]=4[N:22]=[CH:21][CH:20]=[CH:19]5)[CH2:27][CH2:28]3)=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Reactant: COc1ccc2c(CCI)coc2c1
Product: COc1ccc2c(CCN3CCN(c4cc(Cl)cc5cccnc45)CC3)coc2c1

Procedure:
8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 9, step 6, starting from 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil Yield: 140 mg (33%); (M+H): 422; 1HNMR (400 MHz, CDCl3):δ 8.86˜8.68 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.02˜7.99 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.45˜6.63 (m, 7H); 3.9 (s, 3H); 3.65˜2.71 (m, 12H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]1>>[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:25][CH2:26]1
Reactant: Clc1cc(-c2ccccc2)ccn1
Reactant: NCCCCN1CCN(c2ccccc2F)CC1
Product: Fc1ccccc1N1CCN(CCCCNc2cc(-c3ccccc3)ccn2)CC1
Yield: 10 %

Procedure:
{2-{4-[4-(2-Fluorophenyl)piperazin-1-yl]butyl}amino-4-phenylpyridine is prepared by reacting 2-chloro-4-phenylpyridine (preparation described in EP 036 638) and 4-[4-(2-fluorophenyl)piperazin-1-yl]butylamine (Example 1, step b) using the same method as described in Example 1, step d.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][CH:11]2[CH:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][F:22])[S:10]2)[C@H:6]1[O:23]C(=O)C)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[F:22][CH2:21][CH2:20][NH:19][C:9]1[S:10][CH:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:23])[CH:7]2[N:8]=1
Reactant: CC(=O)OC[C@H]1OC2SC(NCCF)=NC2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC[C@H]1OC2SC(NCCF)=NC2[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
(5R,6S,7R)-5-(acetoxymethyl)-2-(2-fluoroethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diyl diacetate (0.074 g, 0.19 mmol) was dissolved in anhydrous MeOH. K2CO3 was added to the solution until it was basic, and the reaction was stirred at room temperature (1.5 h). The reaction was filtered and then concentrated in vacuo. The crude material was purified via flash column chromatography with a solvent system of 5:1 DCM and MeOH, providing (5R,6S,7R)-2-(2-fluoroethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (35) (0.045 g, 90% yield). 1H NMR (500 MHz, methanol-d4) δ 3.47-3.67 (m, 5H), 3.78 (dd, 1H, J=2.1, 11.8 Hz), 3.92 (t, 1H, J=5.6 Hz), 4.06 (t, 1H, J=6.1 Hz), 4.40-4.50 (m, 1H), 4.50-4.56 (m, 1H), 6.31 (d, 1H, J=6.4 Hz). 13C NMR (125 MHz, methanol-d4) δ 62.02, 69.93, 74.41, 75.15, 81.31, 82.64, 89.84, 89.87, 162.00.
Reaction SMILES: [OH:1][CH:2]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:28][CH:27]=1)[CH:3]([NH:18][C:19](=O)[O:20]C(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[F:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55](C(O)=O)=[CH:54][CH:53]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[C:55]([C:19]([NH:18][CH:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:14])[F:15])[CH:6]=2)[CH:2]([OH:1])[C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)=[O:20])=[CH:54][CH:53]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2cccnc2)cc1)c1ccc(F)c2ccccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To tert-butyl (1RS,2SR)-2-hydroxy-2-[4-(pyridin-3-yloxy)phenyl]-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethylcarbamate (500 mg, 0.93 mmol) was added trifluoroacetic acid (10 ml), and the mixture was stirred at 0° C. for 10 min. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate (30 ml×2). The extract was washed with saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. To a solution of the residue in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (177 mg, 0.93 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (268 mg, 1.40 mmol) and 1-hydroxybenzotriazole hydrate (143 mg, 0.93 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (150 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1). Recrystallization from ethyl acetate-hexane gave the objective substance (347 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](=O)[CH2:25][F:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][F:26])[CH2:23][Cl:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:6]=2[CH:21]=1
Reactant: O=C(CF)CCl
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Solvent: C1CCOC1
Product: FCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-chlorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-3-fluoropropanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(fluoromethyl)ethylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:17][C:16]=2[C:27]([F:30])([F:29])[F:28])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:62]([NH:65][CH2:66][CH2:67]O)(=[O:64])[CH3:63]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([O:25][CH2:67][CH2:66][NH:65][C:62](=[O:64])[CH3:63])=[O:24])=[CH:17][C:16]=2[C:27]([F:30])([F:28])[F:29])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: CC(=O)NCCO
Reactant: CC(Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3)c(C(F)(F)F)c1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCCOC(=O)C(C)Cc1ccc(OCc2cc(Cl)cc3c2OC(C)(C)C3)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
A solution of 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoic acid (38) (50 mg, 0.113 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (54.3 mg, 0.169 mmol), and diisopropylethylamine (39.3 μL, 0.225 mmol) in DMF (1.5 mL) was stirred at room temperature for 30 min, then N-acetylethanolamine (23 mg, 0.226 mmol) was added. The reaction mixture was stirred at room temperature overnight. After evaporation of solvent in vacuo, the residue was purified by preparative HPLC to afford 2-acetamidoethyl 3-(4-((5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)-3-(trifluoromethyl)phenyl)-2-methylpropanoate (155) (45 mg, 70%). 1H NMR (400 MHz, CDCl3) δ: 7.39 (s, 1H), 7.04 (m, 2H), 7.05-7.00 (m, 2H), 5.47 (br, 1H), 5.06 (s, 2H), 4.10 (m, 2H), 3.44-3.37 (m, 2H), 3.05 (s, 2H), 2.96-2.91 (m, 1H), 2.76-2.66 (m, 2H), 1.93 (s, 3H), 1.49 (s, 6H), 1.19 (d, J=6.8 Hz, 3H). LC-MS ESI m/z: found 528.0 [M−H]−.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([CH:11]=[C:12]([CH3:14])[CH3:13])=[C:8]([CH3:10])[CH:9]=1)=[O:4].[Li+].[OH-]>CO.C(OCC)C>[CH3:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[S:6][C:7]=1[CH:11]=[C:12]([CH3:14])[CH3:13]
Reactant: COC(=O)c1cc(C)c(C=C(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)=Cc1sc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A solution of 4-methyl-5-(2-methyl-propenyl)-thiophene-2-carboxylic acid methyl ester (4.08 g, 19.4 mmol) in methanol (33 mL) is treated with 2 N aq. LiOH solution (10 mL). The mixture is stirred at rt for 2 h, then at 45° C. for 3 h. The reaction mixture is diluted with diethyl ether. The org. layer is separated and extracted with water. The combined aq. phase is acidified with 1 M aq. HCl, and extracted twice with diethyl ether. The combined second org. extracts are dried over MgSO4, filtered and concentrated to give 4-methyl-5-(2-methyl-propenyl)-thiophene-2-carboxylic acid (3.05 g) as an off-white solid; LC-MS: tR=0.92 min, [M+1]+=196.98.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:6].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>CN1CCN(C)C1=O>[CH3:1][NH:2][CH2:3][CH2:4][CH:5]([O:6][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CNCCC(O)c1ccccc1
Reactant: Cc1ccccc1F
Solvent: CN1CCN(C)C1=O
Product: CNCCC(Oc1ccccc1C)c1ccccc1

Procedure:
reacting an alkoxide of N-methyl-3-phenyl-3-hydroxypropylamine with 2-fluorotoluene in 1,3-dimethyl-2-imidazolidinone to give N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine;
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[N:13]1[CH:18]=[C:17]([CH:19]=O)[CH:16]=[N:15][CH:14]=1>>[N:13]1[CH:18]=[C:17](/[CH:19]=[N:10]/[NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)[CH:16]=[N:15][CH:14]=1
Reactant: O=Cc1cncnc1
Reactant: NNc1cccc(C(F)(F)F)c1
Product: FC(F)(F)c1cccc(N/N=C/c2cncnc2)c1
Yield: 87 %

Procedure:
In analogy to the procedure described in Example 167A], 3-(trifluoromethyl)phenylhydrazine and pyrimidine-5-carbaldehyde gave the title compound as a yellow solid (87%). MS: 267.1 (MH+).
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:8][C:7]([CH3:10])([CH3:9])[N:6]=[C:5](SC)[N:4]=1.[CH2:13]([OH:15])[CH3:14]>>[NH2:2][C:3]1[NH:8][C:7]([CH3:10])([CH3:9])[N:6]=[C:5]([O:15][CH2:13][CH3:14])[N:4]=1
Reactant: CSC1=NC(C)(C)NC(N)=N1
Reactant: CCO
Agent: [Na]
Product: CCOC1=NC(C)(C)NC(N)=N1

Procedure:
To a solution of sodium (2.3 g., 0.1 gr. atom) in absolute ethanol (100 ml.) is added 2-amino-3,4-dihydro-4,4-dimethyl-6-methylthio-1,3,5-triazine (3.4 g., 0.02 mole) and the mixture is heated at reflux for 18 hours. The ethanol is distilled at reduced pressure and the residue dissolved in water (100 ml.) and extracted with ethyl acetate (3×100 ml.) dried over potassium carbonate and evaporated in vacuo to give 1.3 g of 2-amino-3,4-dihydro-4,4-dimethyl-6-ethoxy-1,3,5-triazine which melts at 175°-8° C. after crystallization from acetonitrile.
Reaction SMILES: [C:1]1([N:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8](=[O:28])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C(O)C>[C:29]1([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8](=[O:28])[O:9][CH2:10][CH:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:12]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc2c1CCC(COC(=O)N(c1ccccc1)c1ccccc1)C2
Yield: 84.8 %

Procedure:
A solution of [5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-2-naphthyl]methyl N,N-diphenylcarbamate (59 mg) and 1N sodium hydroxide solution (0.15 ml) in ethanol (1.5 ml) was stirred at room temperature for 1 hour and neutralized with 1N hydrochloric acid (0.15 ml), then extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was powdered from n-hexane to afford [5-(carboxymethoxy)-1,2,3,4-tetrahydro-2-naphthyl]methyl N,N-diphenylcarbamate (47 mg) as a colorless powder. mp: 137°-141.5° C.