Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1nn(Cc2ccc(OC)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
To a solution of 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (8.8 g, 47.5 mmol) in MeCN (100 ml) was added K2CO3 (7.9 g, 57.0 mmol) followed by 4-methoxybenzyl chloride (7.1 ml, 52.3 mmol) and the mixture stirred at ambient temperature for 20 hours. The mixture was evaporated in vacuo, the residue partitioned between EtOAc and 2M aqueous hydrochloric acid and the organic portion washed with saturated aqueous sodium hydrogen carbonate, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography [SiO2, EtOAc-hexane (1:4)] to give 1-(4-methoxy-benzyl)-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (11 g) as a colourless gum.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:32])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:26]([CH2:27][C:28]([O:30]C)=[O:29])[N:25]=[N:24][CH:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.Cl>C(#N)C>[ClH:1].[C:28]([CH2:27][N:26]1[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:3][CH2:4]3)=[O:32])[CH2:19][CH2:18][CH:17]\2[SH:20])=[CH:23][N:24]=[N:25]1)([OH:30])=[O:29]
Reactant: COC(=O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CC#N
Product: O=C(O)Cn1nncc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 89.6 %

Procedure:
Following a procedure similar to that described in Example 134, (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-5-yl]methylidene}-4-sulfanylpiperidine hydrochloride (200 mg) was treated with hydrochloric acid and the residue obtained by concentration was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N hydrochloric acid, 25/75, v/v) to afford the title compound (174 mg, yield: 90%) as a colourless amorphous solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][C:3]1=2.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:51].Cl>>[ClH:51].[ClH:51].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:22]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)cc31)CNCC2
Yield: 26 %

Procedure:
tert-Butyl 5-methyl-7-(2-oxo-4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (165 mg, 0.315 mmol) was deprotected and converted to the dihydrochloride salt according to the procedure of Example 30 (steps e and g) to provide the title compound (40 mg, 26%) as a yellow solid 1H NMR (300 MHz, CD3OD) δ 9.10 (d, J=2.0 Hz, 1H), 8.41 (dd, J=8.2, 1.7 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H), 7.57 (d, J=1.6 Hz, 1H), 7.14 (dd, J=8.3, 1.9 Hz, 1H), 7.02 (d, J=1.6 Hz, 1H), 6.89 (dd, J=7.1, 2.0 Hz, 1H), 4.49 (s, 2H), 3.76 (s, 3H), 3.68 (t, J=6.2 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H); ESI MS m/z 425 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.3 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21]([O:26]C)[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]([CH3:37])[CH3:36])[CH:29]=2)([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[OH:9])=[CH:4][CH:3]=1.Cl>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:9])([C:10]2[N:11]([CH3:15])[CH:12]=[N:13][CH:14]=2)[C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH:35]([CH3:37])[CH3:36])[CH:29]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cccc(OC(C)C)c2)c2cc(C(O)(c3ccc(Cl)nc3)c3cncn3C)ccc2n1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)nc4)c4cncn4C)cc23)c1
Yield: 28.5 %

Procedure:
Following the same procedure as described in example 1F, 6-[(6-chloro-pyridin-3-yl)-[4-(3-isopropoxy-phenyl)-2-methoxy-quinolin-6-yl]-(3-methyl-3H-imidazol-4-yl)-methanol (75 mg, 0.14 mmol) was treated with HCl in aqueous THF to yield the title compound (20 mg, 27% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1.C(N(C(C)C)CC)(C)C.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH3:15])[CH3:14])=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Reactant: COC(=O)CNCc1ccc(N(C)C)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccc(N(C)C)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 49.4 g (222 mmol) of [(4-dimethylamino-benzylamino)-acetic acid methyl ester], 41.4 ml (244 mmol) of diisopropylethyl amine and 0.271 g (2.2 mmol) of DMAP in 600 ml of CH2Cl2, 54.8 g (222 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 100 ml of CH2Cl2 are added at 0-5° C. After stirring for 15 h at r.t., the reaction mixture is quenched with ice water and sat. aqueous NH4CO3. The mixture is extracted with AcOEt and combined extracts are washed with sat. aqueous NH4CO3 and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane:AcOEt=4:1) to give the title compound as a colorless solid.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]2[CH2:9][CH2:8]2)[C:5]2[CH:10]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:11]([C:14]3[CH:19]=[C:18]([Cl:20])[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1.C(Cl)Cl.CO.N>>[Cl:20][C:18]1[C:17](=[O:21])[N:16]([CH3:22])[CH:15]=[C:14]([N:11]2[C:12](=[O:13])[C:4]3[CH:3]=[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:31][CH3:30])=[N:37][CH:36]=4)[N:6]([CH:7]4[CH2:9][CH2:8]4)[C:5]=3[CH:10]2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cn1cc(N2C(=O)c3cc(Br)n(C4CC4)c3C2c2ccc(Cl)cc2)cc(Cl)c1=O
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ncc(-c2cc3c(n2C2CC2)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)cn1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 240 but using 2-bromo-5-(5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(4-chlorophenyl)-1-cyclopropyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (Step 243.1) and (2-methoxypyrimidin-5-yl)boronic acid. tR: 0.97 min (LC-MS 6); ESI-MS: 522.1 [M+H]+ (LC-MS 6); TLC (CH2Cl2/MeOH/NH3 94:5:1): Rf=0.38; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.18-0.40 (m, 1 H) 0.60-0.85 (m, 2 H) 1.09-1.19 (m, 1 H) 3.10-3.20 (m, 1 H) 3.42 (s, 3 H) 3.92 (s, 3 H) 6.33 (s, 1 H) 6.62 (s, 1 H) 7.32 (m, J=8.60 Hz, 2 H) 7.40 (m, J=8.60 Hz, 2 H) 7.80-7.97 (m, 2 H) 8.81 (s, 2 H).
Reaction SMILES: [CH:1]([C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:16]([O:18]C)=[O:17])[S:6][C:5]=2[CH:4]=1)=[O:2].[OH-].[K+].CO.Cl>O>[CH:1]([C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[S:6][C:5]=2[CH:4]=1)=[O:2]
Reactant: COC(=O)c1cc2c(cc(C=O)c3ccccc32)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=Cc1cc2sc(C(=O)O)cc2c2ccccc12

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser and N2 inlet line with bubbler was added methyl 5-formylnaphtho-[2,1-b]thiophene-2-carboxylate (7A, 9.75 g, 36 mmol), KOH (85%, Mallinckrodt Co., St. Louis, Mo. 63147, 18.0 g, 320 mmol), CH3OH (40 mL) and H2O (80 mL). The mixture was refluxed for 1.5 h, cooled and neutralized with 3N HCl (500 mL). A yellow solid formed which was filtered and washed with H2O (3×300 mL) and dried in a vacuum oven overnight to give crude 5-formylnaphtho-[2,1-b]thiophene-2-carboxylic acid in quantitative yield. This material was then slurried with quinoline (Mallinckrodt, 60 mL) and cuprous oxide (MCB, 6.2 g, 43.3 mmol) and heated to 185° in an oil bath for 1 h. The reaction mixture was allowed to cool to RT then partitioned between Et2O (500 mL) and concentrated HCl (200 mL) containing saturated NH4Cl (100 mL). The layers were separated and the aqueous layer extracted with additional Et2O (500 mL). The Et2O layers were combined and washed in succession with 1N HCl (300 mL), H2O (2×300 mL) and saturated NaCl solution (2×300 mL), dried (MgSO4), filtered and concentrated to give a light brown crude solid. After chromatography on SiO2 using CHCl3 /hexane as the eluting solvent and crystallization (CHCl3 /cyclohexane) there was obtained 4.98 g (65.2% yield) of naphtho[2,1-b]thiophene-5-carbaldehyde, mp 101°-102°, (C,H,S).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]=1Cl)=[O:5])C.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>C1(C)C(C)=CC=CC=1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:4](=[O:5])[C:6]3=[N:7][NH:8][C:9]4[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=4[C:15]3=[N:26]2)=[CH:21][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)c1nnc2c(c1Cl)CCCC2
Agent: Cl
Solvent: Cc1ccccc1C
Product: O=c1c2n[nH]c3c(c-2nn1-c1ccc(F)cc1)CCCC3
Yield: 23 %

Procedure:
4-Chloro-5,6,7,8-tetrahydrocinnoline-3-carboxylic acid ethyl ester (0.5 g), 4-fluorophenylhydrazine hydrochloride (0.34 g) and H{umlaut over (u)}inig's base (0.73 ml) in xylene under nitrogen were heated under reflux for 2 h. The solid was collected by filtration, washed with diethyl ether, water and diethyl ether. The residue was recrystallised from ethanol to give the title compound (136 mg, 13%). δH (360 MHz; DMSO-d6) 1.83 (4H, m, CH2), 2.67 (2H, t, J=5.3 Hz, CH2), 2.72 (2H, t, J=5.3 Hz, CH2), 3.78 (3H, s, OCH3), 7.02 (2H, d, J=9 Hz, ArH), 8.06 (2H, d, J=9 Hz, ArH), m/z (ESP+) 285 (MH+). C15H13FN4O requires C, 63.37; H, 4.61; N, 19.71; found C, 62.96; H, 4.36; N, 19.48%.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]([C:6]#[N:7])[CH3:5].[N+:12]([O-])([OH:14])=[O:13]>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[CH:4]([C:6]#[N:7])[CH3:5]
Reactant: CC(C#N)c1ccccc1F
Reactant: O=[N+]([O-])O
Product: CC(C#N)c1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C

Procedure:
To 24 g of 2-fluoro-α-methylbenzyl cyanide was added dropwise 40 ml of fuming nitric acid while maintaining the temperature 0°-5° C. After addition, the mixture was gradually warmed up to room temperature, poured into ice-water and extracted with ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate and the solvent was evaporated off. The crude crystals obtained were recrystallized from benzene--n-hexane to afford 25.8 g of 2-fluoro-α-methyl-5-nitrobenzyl cyanide, m.p. 55°-56° C.
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:18]([CH2:19][CH2:20][C@:4]23[CH3:5])[C:17]2[CH:16]=[CH:15][C:14](O)=[CH:13][C:12]=2[CH2:11][C@H:10]4CCCCCO)[O:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[CH3:5][C@:4]12[CH2:20][CH2:19][C@H:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=43)[C@@H:6]1[CH:7]=[CH:8][C:3]2=[O:2]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCO)[C@H]3[C@@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H]3c4ccccc4CC[C@H]3[C@@H]1C=CC2=O

Procedure:
A solution of 36.12 g of 17,17-ethylenedioxy-7α-(5-hydroxypentyl)-estra-1,3,5(10),15-tetraen-3-ol in 958 ml of acetone and 111 ml of water is stirred for 2 hours at room temperature with 2.76 g of para-toluenesulfonic acid. Then, it is concentrated by evaporation in a vacuum to ⅓ of the volume, taken up with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated by evaporation in a vacuum. 31.7 g of 3-hydroxy-7α-5-hydroxypentyl)-estra- 1,3,5(10),15-tetraen- 17-one is obtained as crystals with a melting point of 194-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>C(O)C.O.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[CH3:23])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
4-(2-Methyl-5-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.145 g, 0.45 mmol) was dissolved in a mixture of 10 mL of ethanol and 10 mL of water. Ammonium formiate (0.284 g, 0.4 mmol) and 10% Pd/C (0.048 g) were added and the reaction mixture was stirred for 8 h at 40° C. The reaction mixture was then filtered over Celite and the solvent was evaporated to yield 0.064 g of the title compound which was used in subsequent steps without further purification.
Reaction SMILES: [CH2:1]([N:8](C)[S:9]([CH2:12][C:13]([NH2:15])=[O:14])(=[O:11])=[O:10])C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][S:9]([CH2:12][C:13]([NH2:15])=[O:14])(=[O:11])=[O:10]
Reactant: CN(Cc1ccccc1)S(=O)(=O)CC(N)=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNS(=O)(=O)CC(N)=O
Yield: 104.1 %

Procedure:
A solution of (N-benzyl-N-methylsulfamoyl)acetamide (see Example 1(b), 13.0 g, 50.5 mmol) in methanol (130 ml) was hydrogenated over Pearlman's catalyst (7.5 g) at 60° C. and at 345 kPa (50 psi) for 24 hr. The solution was then filtered through a pad of celite (trade mark) which was subsequently washed with acetone (50 ml). The combined filter was evaporated in vacuo to give a white solid which was dried in vacuo at 50° C. overnight to yield the subtitle compound (8.0 g, 98%) as a white solid. m.p. 104-108° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:34]=[CH:33][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:28][CH2:29][CH3:30])=[C:21]([NH:24]C(=O)C)[CH:22]=3)[N:17]=[CH:16][C:15]=2[C:31]#[N:32])=[CH:11][C:10]=1[Cl:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[NH2:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:28][CH2:29][CH3:30])[N:17]=[CH:16][C:15]([C:31]#[N:32])=[C:14]2[NH:13][C:12]1[CH:33]=[CH:34][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]([Cl:35])[CH:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1NC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccc4)c(Cl)c3)c2cc1N
Yield: 88.9 %

Procedure:
A solution of 298 mg (0.612 mmoles) of the purified N-{4-[4-(benzyloxy)-3-chloroanilino]-3-cyano-7-ethoxy-6-quinolinyl}acetamide (example 6) and 97 mg (1.73 mmoles) of potassium hydroxide in 10 ml of methanol was stirred and refluxed for 60 hours. On cooling a solid formed. This mixture was poured onto ice, and the resulting solid was filtered and washed with water. On drying, 242 mg of the title compound was obtained.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([O:28]C)[N:22]=2)=[CH:13]\[C@@H:14]2[N:18]([CH3:19])[C:17](=[O:20])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].O>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:21]2[NH:22][C:23](=[O:28])[C:24]([Cl:27])=[CH:25][CH:26]=2)=[CH:13]\[C@H:14]2[CH2:15][CH2:16][C:17](=[O:20])[N:18]2[CH3:19])=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1nc(/C(=C/[C@H]2CCC(=O)N2C)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: Br
Solvent: O
Solvent: C1COCCO1
Product: CN1C(=O)CC[C@@H]1/C=C(\c1ccc(C(C)(C)C)cc1)c1ccc(Cl)c(=O)[nH]1
Temperature: 65 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
48% hydrobromic acid (3 mL) was added to a solution of (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethenyl]-1-methylpyrrolidin-2-one (152 mg) in 1,4-dioxane (6 mL), and the mixture was stirred at 65° C. for one hour. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-silica gel column chromatography (chloroform:methanol=100:0→98:2) to give a colorless powder (151 mg). This was recrystallized from ethyl acetate-hexane to give the title compound as a colorless powder (99 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Clc1ccc2c(I)n[nH]c2c1
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
In a round-bottomed flask, 6-chloro-3-iodo-1H-indazole (250 mg, 0.85 mmol) was dissolved in THF (5 ml) and sodium hydride (60% dispersion in mineral oil, 41 mg, 1.03 mmol) was added. The reaction mixture was stirred at room temperature for 10 min then cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0 M in THF, 0.52 ml, 1.04 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 30 min then additional isopropylmagnesium chloride (2.0 M in THF (0.14 ml, 0.28 mmol) was added. The reaction mixture was stirred at −16° C. for 10 min then tributylchlorostannane (0.28 ml, 1.03 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature over 2.5 h then quenched with saturated NH4Cl-solution and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered, concentrated to give 6-chloro-3-tributylstannanyl-1H-indazole as a yellow oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]([C:6](OC)=[O:7])=[C:4]([F:13])[CH:3]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]([CH2:6][OH:7])=[C:10]([OH:12])[CH:11]=1
Reactant: COC(=O)c1c(O)cc(Br)cc1F
Solvent: C1CCOC1
Product: OCc1c(O)cc(Br)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl 4-bromo-2-fluoro-6-hydroxybenzoate (0.34 g, 1.4 mmol) was dissolved in dry THF (20 ml) under a blanket of nitrogen. The solution was cooled down to 0° C. and borane tetrahydrofuran complex (5.0 ml, 5.0 mmol) was slowly added. The mixture was stirred at 0° C. for 30 min and at ambient temperature for 15 min. Then it was cooled once more to 0° C. and carefully quenched with water, acidified with aqueous HCl (5%) and finally extracted several times with EtOAc. The combined organic phases were dried (Na2SO4), filtered and evaporated to dryness (0.33/g) to afford the title compound. No further purification was done on this intermediate. ESIMS: m/z 223 (M+H)+, 221 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][N:10]([CH2:17][CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])C(=O)C(F)(F)F)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.C(OCC)C>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:10][CH2:17][CH:18]([OH:23])[C:19]([F:22])([F:20])[F:21])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN(CC(O)C(F)(F)F)C(=O)C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C)c1ccc(CNCC(O)C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 24 h

Procedure:
99 mg of [rac]-N-(4-tert-butyl-benzyl)-2,2,2-trifluoro-N-(3,3,3-trifluoro-2-hydroxy-propyl)-acetamide (0.27 mmol) were dissolved in 0.5 ml ethanol, treated with 0.4 ml 2N NaOH (0.8 mmol) and heated to 75° C. (bath temperature) for 4 h. After this period a second portion of 0.4 ml 2N NaOH (0.8 mmol) was added and the reaction mixture stirred at 7° C. (bath temperature) for additional 24 h. Then the reaction mixture was cooled down to rt, diluted with diethylether, treated with 1.6 ml 1N HCl and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 87 mg of [rac]-(4-tert-butyl-benzyl)-(3,3,3-trifluoro-2-hydroxy-propyl)-amine as an off-white solid (>100%). The crude material was used without further purification in the next step.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[C:50]([Cl:51])=[C:49]([F:52])[CH:48]=[CH:47][C:46]=1[F:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:53])=[CH:47][CH:48]=[C:49]([F:52])[C:50]=3[Cl:51])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1ccc(F)c(CBr)c1Cl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(F)ccc(F)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-3-chloro-1,4-difluorobenzene and isolated as white solid (7.0 mg, 38%). MS (m/e): 443.4 (MH+).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]([OH:6])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[C:52]([C:57]2([C:70]([F:73])([F:72])[F:71])[O:61][N:60]=[C:59]([C:62]3[S:66][C:65]([CH2:67][NH2:68])=[C:64]([CH3:69])[CH:63]=3)[CH2:58]2)[CH:53]=[C:54]([Cl:56])[CH:55]=1>ClCCl>[Cl:49][C:50]1[CH:51]=[C:52]([C:57]2([C:70]([F:71])([F:73])[F:72])[O:61][N:60]=[C:59]([C:62]3[S:66][C:65]([CH2:67][NH:68][C:4](=[O:6])[CH2:3][S:2][CH3:1])=[C:64]([CH3:69])[CH:63]=3)[CH2:58]2)[CH:53]=[C:54]([Cl:56])[CH:55]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1CN
Reactant: CSCC(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSCC(=O)NCc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reaction time: 1 h

Procedure:
(Methylthio)acetic acid (29 μl), PyBOP (126 mg) and Hünig base (115 μl) is added to a solution of C-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-yl}-methylamine (90 mg) in dichloromethane (2 ml). After 1 hour at room temperature, the reaction is quenched with water. The reaction mixture is extracted three times with dichloromethane. The combined organic phases are extracted with a saturated solution of NaHCO3 and with a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo. The crude product is purified on a semi-preparative HPLC to yield N-{5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophen-2-ylmethyl}-2-methylsulfanyl-acetamide (82 mg, compound 1.10 in Table 1) as a white foam. MS (HPLC/MS): 497 (MH+). Retention time: 2.00 min.