Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]([CH2:23][C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([O:28]C)=[O:27])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:9][CH2:8]2)=[N:5][N:6]=1.[OH-].[Na+].Cl>CO>[NH2:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:8][CH2:9][CH:10]([N:13]([CH2:23][C:24]3[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=3[C:26]([OH:28])=[O:27])[CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:11][CH2:12]2)[NH:5][N:6]=1
Reactant: COC(=O)c1ccccc1CN(CCc1ccc(Cl)cc1)C1CCN(c2nnc(N)[nH]2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1n[nH]c(N2CCC(N(CCc3ccc(Cl)cc3)Cc3ccccc3C(=O)O)CC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methyl 2-(((1-(5-amino-4H-1,2,4-triazol-3-yl)piperidin-4-yl)(4-chlorophenethyl)amino)-methyl)benzoate obtained in Step 3 was dissolved in methanol (10 mL) and 3 mL of 1 N NaOH (aq) was added. The reaction mixture was stirred for 5 hours at room temperature after which time the starting material was no longer present. pH of the reaction mixture was brought to 7 by means of careful addition of 1 N HCl and the solvents were stripped off. The solid residue was passed through the reversed phase C-18 column and the product containing fractions were combined and freeze-dried to give the desired product in a form of white solid (95 mg, 22% yield)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[N:4][C:5]([F:11])=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9].[Cl:13][C:14]([Cl:24])=[CH:15][C@@H:16]1[C@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22]>>[Cl:13][C:14]([Cl:24])=[CH:15][C@@H:16]1[C@H:18]([C:19]([O:9][CH2:8][C:7]2[C:2]([Cl:1])=[C:3]([F:12])[N:4]=[C:5]([F:11])[C:6]=2[Cl:10])=[O:20])[C:17]1([CH3:22])[CH3:23]
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OCc1c(Cl)c(F)nc(F)c1Cl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1c(Cl)c(F)nc(F)c1Cl

Procedure:
By the method of Example 2, 0.5 g (0.002 mole) of 3,5-dichloro-2,6-difluoro-4-hydroxymethylpyridine (Example 15) was reacted with 0.5 g (0.002 mole) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce, after purification using the Chromatotron, 0.3 g of (3,5-dichloro-2,6-difluoropyridin-4-yl)methyl cis-3-(2,2-di-chloroethenyl)-2,2-dimethylcyclopropanecarboxylate, compound 22 in the Tables below.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:21]([O:23][NH2:24])[CH3:22]>CO>[CH2:21]([O:23][N:24]=[C:1]([C:6]1[C:7](=[O:19])[O:8][C:9]2([CH2:18][S:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:22]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC2(CSCCSC2)OC1=O
Agent: Cl
Solvent: CO
Product: CCCC(=NOCC)C1=C(O)CC2(CSCCSC2)OC1=O
Yield: 32.8 %

Procedure:
The acylated compound (8.52) (0.453 g, 1.50 mmol) was oximated with ethoxyamine hydrochloride (0.195 g, 2.00 mmol) in methanol (10 ml) as described in Part (c) of the general procedure above to afford a product which was recrystallized from ether to give the title compound (6.25) (0.170 g, 33%) as white microcrystals m.p. 108°-110° C. Mass spectrum m/z 346 (M+1). 1H n.m.r. δ(CDCl3) 4.11, q, J 7 Hz, OCH2CH3 ; 3.95-1.1, complex, 14H; 1.33, t, J 7 Hz, OCH2CH3 ; 1.00, t, J 7 Hz CH2CH2CH3.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22](O)=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH3:33][N:34](C)[CH:35]=O>C(Cl)Cl>[N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][C:22]([N:34]([CH3:35])[CH3:33])=[O:23])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@H]1C[C@@H](CC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)S[C@H]1C[C@@H](CC(=O)N(C)C)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-carboxymethyl-4-acetylthiopyrrolidine (125 mg) was dissolved in 1 ml of dry methylene chloride, and 0.1 ml of oxalyl chloride and a catalytic amount of dimethylformamide were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was distilled to remove the solvent, and dry benzene was added to the residue, followed by distillation of benzene. After two times repetition of the above procedure, the resulting residue was dissolved in 2 ml of dry methylene chloride. The resultant mixture was added to a solution of 45 mg of dimethylamine in 1.5 ml of dry methylene chloride and 0.2 ml of dry tetrahydrofuran under nitrogen stream at 0° C., followed by stirring at the same temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. The residue was purified by silica gel thin layer chromatography to obtain (2R,4S)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylaminocarbonylmethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3](Cl)=[O:4].[OH:38][C:39]1[CH:81]=[CH:80][C:42]([C:43]2[CH:48]=[CH:47][C:46]([C:49]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]4[CH:55]=[CH:54][C:53]([C:74]5[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=5)([C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:73][CH2:72][CH2:71][CH2:70]6)=[CH:65][CH:64]=5)[O:52][C:51]=4[CH:50]=3)=[CH:45][CH:44]=2)=[CH:41][CH:40]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:37])([C:6]([F:36])([F:35])[C:7]([F:34])([F:33])[C:8]([F:32])([F:31])[C:9]([F:30])([F:29])[C:10]([F:28])([F:27])[C:11]([F:26])([F:25])[C:12]([F:24])([F:23])[C:13]([F:22])([F:21])[C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:3]([O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]2[CH:44]=[CH:45][C:46]([C:49]3[C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:56]4[CH:55]=[CH:54][C:53]([C:74]5[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=5)([C:63]5[CH:68]=[CH:67][C:66]([N:69]6[CH2:73][CH2:72][CH2:71][CH2:70]6)=[CH:65][CH:64]=5)[O:52][C:51]=4[CH:50]=3)=[CH:47][CH:48]=2)=[CH:80][CH:81]=1)=[O:4]
Reactant: Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc(-c2ccc(-c3cc4c(c5ccccc35)C=CC(c3ccccc3)(c3ccc(N5CCCC5)cc3)O4)cc2)cc1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 45.8 %

Procedure:
Solid 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-tricosafluorododecanoyl chloride (0.37 g, 0.58 mmol) was added to a solution of 6-[4′-(hydroxy)biphen-4-yl]-3-phenyl-3-(4-pyrrolidinophenyl)-3H-naphtho[2,1-b]pyran (0.33 g, 0.58 mmol) in DCM (100 mL) containing 4-dimethylaminopyridine (0.05 g) and pyridine (2 mL) under N2 with stirring. The mixture was stirred at room temperature for 3 h, poured into HCl (2 M, 100 mL), extracted with EtOAc (3×30 mL), washed with water (100 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was filtered through a short plug of silica using DCM (60% in hexanes as eluent), the solvent removed under reduced pressure. Hexane was added and the resulting solid filtered to give the title compound (0.31 g, 46%) as a colourless powder, mp 129-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]3)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:35][Mg]Br>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([N:21]3[CH2:25][CH2:24][C:23]([OH:26])([CH3:35])[CH2:22]3)(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=C1CCN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Solvent: C1CCOC1
Product: CC1(O)CCN(S(=O)(=O)NC2CCC(c3cc(F)ccc3F)(S(=O)(=O)c3ccc(Cl)cc3)CC2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
The product from Example 182 (65 mg, 0.12 mmol) in tetrahydrofuran (10 ml) at 0° C. was treated with methyl magnesium bromide (3M solution in tetrahydrofuran, 0.4 ml). The reaction was stirred at 0° C. for 45 minutes then quenched with NH4Cl solution, extracted into ethyl acetate and evaporated. The residue was purified by chromatography on silica (diethyl ether) to afford the desired compound (18 mg). 1H NMR (360 MHz, CDCl3) δ 7.38–7.31 (4H, m), 7.07–7.06 (2H, m) 6.89–6.80 (1H, m), 4.90–4.98 (1H, d, J=4 Hz), 3.58–3.55 (2H, m), 3.49–3.40 (2H, m), 3.24–3.23 (1H, m), 2.56–2.39 (4H, m), 2.12 (1H, s), 2.04–1.94 (4H, m), 1.52–1.46 (2H, m), 1.45 (3H, s). m/z=571, 573 [MNa]+
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28](=[O:41])[CH2:29][C:30]1[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[N:32][NH:33][CH:34]=1)[CH3:26].O>CN(C)C=O>[CH3:18][C:17]1[S:16][C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:14][C:13]=1[CH2:12][O:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][N:33]2[CH:34]=[C:30]([CH2:29][C:28]([O:27][CH2:25][CH3:26])=[O:41])[C:31]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:32]2)=[CH:6][CH:7]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)sc3C)nc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.8 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazolylmethoxy)pyridine (579 mg) and ethyl(3-phenyl-1H-pyrazol-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl [1-[6-(5-methyl-2-phenyl-4-thiazolylmethoxy)-3-pyridylmethyl]-3-phenyl-1H-pyrazol-4-yl]acetate (476 mg, yield: 52%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: C(O)(=O)C(O)=O.[CH3:7][N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH:15]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][N:20]3[C:16]2=[N:17][C:18]([CH:29]=[CH2:30])=[CH:19]3)[CH2:10][CH2:9]1>CO.[Pd]>[CH2:29]([C:18]1[N:17]=[C:16]2[N:20]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:15]2[O:14][CH:11]2[CH2:12][CH2:13][N:8]([CH3:7])[CH2:9][CH2:10]2)[CH:19]=1)[CH3:30]
Reactant: C=Cc1cn2c(n1)C(OC1CCN(C)CC1)c1ccccc1CC2
Agent: [Pd]
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCc1cn2c(n1)C(OC1CCN(C)CC1)c1ccccc1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(1-methylpiperidin-4-yloxy)-2-vinyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene oxalate (example 9A) (110 mg, 0.34 mmole) in MeOH (1.7 mL) is added Pd/C 10% (11 mg). The flask is evacuated and filled with hydrogen (balloon). The reaction mixture is stirred at room temperature overnight, then filtered on celite and cake washed with MeOH. Solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) as eluent with a gradient from (98:2:0.2) to (95:5:0.5) and the residue is submitted to a preparative thin-layer chromatography eluting with (CH2Cl2:MeOH:NH4OH) (9:1:1) to afford 2-ethyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([C:38]([F:41])([F:40])[F:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[C:38]([F:40])([F:39])[F:41])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(F)ccc1C(F)(F)F
Product: Fc1ccc(C(F)(F)F)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-fluoro-2-trifluoromethyl-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 555.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)=[N:7][C:6]=12.[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1)#[CH:27]>>[CH3:25][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:5]3[N:4]=[CH:3][C:2]([C:27]#[C:26][C:28]4[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=4)=[C:6]3[N:7]=2)[CH:20]=[CH:19][C:18]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Reactant: C#Cc1ccc(N)nc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(N)nc4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.32) (236 mg, 0.5 mmol) and 5-ethynyl-pyridin-2-ylamine (example D.1) (59 mg, 0.5 mmol) according to general procedure II. Obtained as a red solid (165 mg, 71%). MS (EI) 461.1 [(M)+]; mp 201° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:29])(=O)=O>>[Cl:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(CO)cc1)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCl)cc1)c1ccccn1
Yield: 95.1 %

Procedure:
Reaction of Pyridine-2-carboxylic acid (4-hydroxymethyl-phenyl)amide (342 mg, 1.50 mmol), Et3N (262 uL, 1.80 mmol), and methanesulfonylchloride (128 uL, 1.65 mmol) for 2 h at reflux gave the title compound (352 mg, 95%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.61 (s, 2H), 7.45 (d, 2H, J=8.4 Hz), 7.50 (ddd, 1H, J=7.5, 4.8, 0.9 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.92 (ddd, 1H, J=7.8, 7.8, 1.6 Hz), 8.63 (d, 1H, J=6.0 Hz), 10.08 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11].S(=O)(=O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[C:7]([N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1c(F)cccc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)Cc1c(F)ccc([N+](=O)[O-])c1Cl
Temperature: 0 °C
Yield: 78 %

Procedure:
1.89 g of 2-chloro-6-fluoro-phenylacetic acid was suspended in 20 ml of concentrated nitric acid. After the addition of 10 ml of concentrated sulfuric acid, the resulting mixture was heated under reflux for 3.5 hours. After the reaction mixture was poured into ice water, the resulting precipitate was collected by filtration, washed with a small amount of purified water, and then dried. Thus, 1.83 g (78% yield) of the title compound was obtained as a white powder.
Reaction SMILES: C1COCC1.[Li+].[BH4-].[C:8]([O:12][C:13]([NH:15][C@@H:16]([CH2:21][CH2:22][C:23](OC)=[O:24])[C:17](OC)=[O:18])=[O:14])([CH3:11])([CH3:10])[CH3:9]>CO>[OH:18][CH2:17][C@@H:16]([NH:15][C:13](=[O:14])[O:12][C:8]([CH3:10])([CH3:9])[CH3:11])[CH2:21][CH2:22][CH2:23][OH:24]
Reactant: COC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CCCO
Temperature: 0 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A 20 L reactor was charged with 10 L of dry THF and LiBH4 (400 g) and cooled to 0° C. A THF solution of (S)-dimethyl 2-(tert-butoxycarbonylamino)pentanedioate (1000 g/3.63 mol, dissolved in 2 L of dry THF) was then added dropwise while keeping the internal temp. below 15° C. The mixture was slowly warmed to room temperature and stirred for 16 h. Cooled to 0° C., then MeOH (10 L) was added dropwise to the reaction mixture to quench the excess amount of reducing reagent. Concentrated, and the residue was poured into 5 L water. After extraction with ethyl acetate, the combined organic phase was dried over Na2SO4. After filtration the solvent was removed in vacuo to give 730 g of crude (S)-tert-butyl 1,5-dihydroxypentan-2-ylcarbamate as a pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:15])[C:11]([F:13])([F:14])[F:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCCc1ccccc1)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(CCCc1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
19.5 g (90 mmol) of said product (14-1) was dissolved in 200 ml of ethanol, and the solution was added with 1.7 g (45 mmol) of sodium borohydride and stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate, and the resultantly formed organic layer was washed with water and brine successively, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 19.1 g of 5-phenyl-1,1,1-trifluoro-2-pentanol (15-1) as a colorless liquid. Yield: 97%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]2[CH2:33][CH2:32]2)[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:25][C:26]([NH2:28])=[O:27])=[CH:14][CH:13]=2)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[NH2:7][CH2:8][C:9]1[N:10]([CH2:30][CH:31]2[CH2:32][CH2:33]2)[C:11](=[O:29])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([O:24][CH2:25][C:26]([NH2:28])=[O:27])=[CH:14][CH:13]=2
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC2CC2)c(=O)c2ccc(OCC(N)=O)cc12
Agent: Cl
Solvent: CCOC(C)=O
Product: CCCCOc1c(CN)n(CC2CC2)c(=O)c2ccc(OCC(N)=O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of tert-butyl[6-(2-amino-2-oxoethoxy)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.28 g, 0.6 mmol) in ethyl acetate (5 mL) was added a-solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were recrystallized from methanol-diisopropyl ether to give 2-[[3-(aminomethyl)-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.23 g, 92.0%) as crystals.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:3]([OH:5])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[CH3:1]/[C:2](=[CH:6]\[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)/[C:3]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:5]
Reactant: C/C(=C\Sc1ccccc1)C(=O)O
Reactant: Nc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C/C(=C\Sc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A suspension of 2.5 g (12.8 mmol) of (E)-2-methyl-3-(phenylthio)-2-propenoic acid and 3.5 g (25.7 mmol) of thionyl chloride in 25 ml of toluene was refluxed for 1 hour and then concentrated under vacuum. The residue was dissolved in 25 ml of ethyl acetate and cooled in ice bath. To the solution was added dropwise 2.9 g (32 mmol) of aniline and stirred at room temperature for 30 minutes. The reaction mixture was washed sequentially with 1N HCl solution, a saturated NaHCO3 solution, and a saturated NaCl solution. The organic layer was dried over anhydrous MgSO4 and concentrated to obtain 3.0 g of (E)-2-Methyl-N-phenyl-3-(phenylthio)-2-propenamide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][CH2:11][C@H:12]1[CH2:14][O:13]1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>C1(C)C=CC=CC=1.C(O)C.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:13]1[CH2:14][C@@H:12]1[CH2:11][O:10][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=1)[CH3:9]
Reactant: CC(OC[C@H]1CO1)c1ccccc1Br
Reactant: N#Cc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: CC(OC[C@H]1CO1)c1ccccc1-c1ccc(C#N)cc1
Temperature: 25 °C
Yield: 26.8 %

Procedure:
(R)-2-[1-(2-Bromophenyl)ethoxymethyl]oxirane (8.24 g) was dissolved in toluene (38 ml) and ethanol (150 ml), 2M-aqueous sodium carbonate (80 ml), 4-cyanophenylboronic acid (5.65 g) and tetrakis(triphenylphosphine)palladium(0) (1.85 g) were successively added, and the mixture was heated under reflux overnight. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted 3 times with diethyl ether. The organic layer was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to give the title compound (2.40 g).
Reaction SMILES: [F:1][C:2]([F:31])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([NH:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:5](=[O:14])[NH:6][C@@:7]([CH2:12][OH:13])([CH3:11])[CH2:8][CH2:9][CH3:10].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:31][C:2]([F:1])([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([NH:15][C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:5](=[O:14])[NH:6][C@@:7]([CH:12]=[O:13])([CH3:11])[CH2:8][CH2:9][CH3:10]
Reactant: CCC[C@@](C)(CO)NC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC[C@@](C)(C=O)NC(=O)[C@H](CC(F)(F)Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.4 %

Procedure:
A mixture of Morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-hydroxymethyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amide (217 mg) and Dess-Martin Periodinane (15% in DCM, 2 eq.) in DCM (5 mL) is stirred at room temperature for 3 hrs and quenched with a solution of sodium thiosulfate in saturated NaHCO3. The product is extracted with ethyl acetate and washed with saturated NaCl solution. Organic phase is dried over anhydrous MgSO4, solvent evaporated under reduced pressure. Purification by silica gel chromatography eluting with ethyl acetate-heptane mixture gives Morpholine-4-carboxylic acid [(S)-3,3-difluoro-1-((S)-1-formyl-1-methyl-butylcarbamoyl)-4-phenyl-butyl]-amide (83 mg, 38%).