Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][CH:6]=1)(=O)C.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)Nc1ccc(OC(F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1ccc(OC(F)C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
18.8 g (0.08 moles) 4-acetylaminotetrafluoroethoxybenzene of Step 1 are dissolved, accompanied by ice cooling at 0° C., in 150 ml concentrated sulfuric acid. Nitration is carried out at the same temperature with a mixture of 10.3 ml (0.15 moles) concentrated nitric acid (d=1.4 g/ml) and 10 ml concentrated sulfuric acid. After standing overnight this mixture is poured onto approximately 500 g ice. A viscous oil precipitates. The oily phase is decanted and repeatedly washed with water. The oil is made to solidify by means of cooling and scraping. It is, according to DC, a mixture of acetylaminonitro- and aminonitro-compounds. It is then saponfied by means of dissolving and boiling, with reflux, with methanol and concentrated hydrochloric acid and then neutralized with ammonia. The 4-amino-3-nitrotetrafluoroethoxybenzene precipitates. Yellow crystals with a melting point of 78° C. were obtained. Yield: 13.4 g (67% of the theoretical yield)
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@@H:17]([OH:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Na].O>C(O)C>[OH:1][C@@H:2]1[C@@H:21]([N:22]2[CH2:27][CH2:26][O:25][C:24]([CH3:29])([CH3:28])[CH2:23]2)[CH2:20][C@@:19]2([CH3:30])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C@H:17]([OH:31])[CH2:16][C@@:15]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOC(C)(C)C5)C[C@]4(C)[C@H]3[C@H](O)C[C@]12C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
A portion (4.0 g) of the solid (A) of Example 31 was dissolved in ethanol (140 ml) and sodium (8.5 g) was added portionwise over 4 h. The mixture was poured into water (1.4 l) and the precipitated solid was filtered off, washed with water and dissolved in methanol (40 ml). Methanesulfonic acid (1.6 ml) was added and the solution was stirred at room temperature for 1 h and then poured into water (400 ml). After extraction with ethyl acetate, sodium carbonate was added to the aqueous phase until the pH exceeded 9. The resulting mixture was extracted with dichloromethane and the organic phase was washed with water. After drying over sodium sulfate, the solvent was removed under reduced pressure and the residue was chromatographed on silica gel. The purified product was crystallised from diethyl ether to give (2β,3α,5α,11α)-3,11-dihydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnan-20-one (750 mg). m.p. 182°-185° C.; [α]D +125.6° (c 0.25).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:21](=[O:22])[CH2:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:24])([F:12])[F:25])[CH:15]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1[nH]ccc1C
Product: CCOC(=O)c1[nH]cc(C(=O)Cc2cccc(C(F)(F)F)c2)c1C

Procedure:
3-Methyl-4-[2-(3-trifluoromethylphenyl)-acetyl]-1H-pyrrole-2-carboxylic acid ethyl ester (103) was synthesized from 3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (84) and (3-trifluoromethylphenyl)-acetyl chloride following the procedure described in Example 32. Crude yield: 97%. 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, 3H), 2.62 (s, 3H), 4.11 (s, 2H), 4.35 (q, 2H), 7.45 (m, 2H), 7.51 (m, 3H), 9.40 (s broad, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ 11.73, 14.40, 46.73, 60.78, 123.70, 124.70, 126.82, 128.93, 129.71, 133.01, 135.85, 161.61, 192.58 ppm. DEPT (100 MHz, CDCl3): CH3 carbons: 11.73, 14.40; CH2 carbons: 46.73, 60.78; CH carbons: 123.70, 126.82, 128.93, 129.71, 133.01 ppm. LC/MS: 79.18%, m/z=339.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[CH2:27][NH2:28]>>[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[CH2:27][NH:28][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Reactant: NCC1COc2ccccc2O1
Product: Oc1cccc(Nc2nc(NCC3COc4ccccc4O3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 19.26 min.; purity: 96.2%; MS (m/e): 369.08 (MH+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH:29]([CH3:33])[C:30]([OH:32])=O)=[CH:25][CH:24]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[OH:36][CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[OH:36][CH:37]1[CH2:42][CH2:41][N:40]([C:30](=[O:32])[CH:29]([C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:35])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:28][CH:27]=2)[CH3:33])[CH2:39][CH2:38]1
Reactant: CC(C(=O)O)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1
Reactant: OC1CCNCC1
Product: CC(C(=O)N1CCC(O)CC1)c1ccc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cc1

Procedure:
This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and 4-hydroxypiperidine. LCMS (M+H)+: m/z=567.3
Reaction SMILES: [NH4+:1].[OH-].[C:3]([OH:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([OH:13])=[O:12])([C:7]([OH:9])=[O:8])[OH:6]>>[C:3]([O-:15])(=[O:14])[CH2:4][C:5]([CH2:10][C:11]([O-:13])=[O:12])([C:7]([O-:9])=[O:8])[OH:6].[NH4+:1].[NH4+:1].[NH4+:1]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
Ammonium citrate was prepared by mixing 32.2 ml of NH4OH with 30.93 g of citric acid. This solution was stirred into the residue.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14].[O-:16][C:17]#[N:18].[K+].CO>Cl.O>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:17]([NH2:18])=[O:16]
Reactant: N#C[O-]
Reactant: CN(C)CCCCCCCCCCCN
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(C)CCCCCCCCCCCNC(N)=O
Yield: 21.7 %

Procedure:
A solution of this amine (4.6 g) in dilute hydrochloric acid (40 ml) and concentrated hydrochloric acid (12 ml) was treated with potassium cyanate (7.0 g) in water (10 ml). The mixture was refluxed for 18 hours and the solvent removed leaving a white solid. To this methanol (10 ml) was added and the mixture filtered. The solvent was evaporated from the filtrate which was then chromatographed on a basic alumina column eluting with 10% methanol in chloroform, to give a yellow solid which was washed with ether to give N,N-dimethyl-N-(11-ureidoundecyl)amine as a white solid (1.2g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH:14]=O)[C:6]=2[CH:16]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N+:10]([O-:11])=[N:9][C:8](=[O:12])[N:7]([CH2:13][CH2:14][N:39]3[CH2:38][CH2:37][CH:36]([N:28]([CH2:27][C:24]4[N:23]=[CH:22][C:21]5[O:20][CH2:19][CH2:18][O:17][C:26]=5[CH:25]=4)[C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:34])[CH3:32])[CH2:41][CH2:40]3)[C:6]=2[CH:16]=1
Reactant: O=CCn1c(=O)n[n+]([O-])c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Yield: 42 %

Procedure:
A mixture of (6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)acetaldehyde (89 mg, 0.372 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (117 mg, 0.334 mmol) in chloroform (5 ml) and MeOH (0.5 ml) was stirred for 2 h before addition of NaBH(OAc)3 (212 mg, 1.002 mmol). The reaction was stirred for 1 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 10% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound as a yellow oil (81 mg, 42%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2].[CH3:26][O:27][CH2:28][CH2:29][CH2:30][NH2:31]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:31][CH2:30][CH2:29][CH2:28][O:27][CH3:26])=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([O:24][CH3:25])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3OC)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methoxyphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-methoxypropan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.88 (m, 3H) 3.25 (s, 5H) 3.96 (s, 5H) 7.33-7.56 (m, 3H) 8.31-8.56 (m, 1H) 8.70 (br. s., 1H) 8.91 (s, 1H). MS m/z [M+H]+ 408.4.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:19][C:20](=[O:24])[CH2:21][C:22]#[N:23])([CH3:18])[CH2:13][C:14]([O:16]C)=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C[O-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([CH3:18])[NH:19][C:20](=[O:24])[C:21]([C:22]#[N:23])=[C:14]([OH:16])[CH2:13]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc(C(C)(CC(=O)OC)NC(=O)CC#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCOc1ccc(C2(C)CC(O)=C(C#N)C(=O)N2)cc1
Temperature: 55 °C
Yield: 101.5 %

Procedure:
To a stirred solution of Intermediate 107D (218 mg, 0.656 mmol) in MeOH (5 mL) was added 4.37 M NaOMe (0.750 mL, 3.28 mmol) in methanol solution. The reaction was heated to 55° C. for 5 h. The reaction mixture was concentrated and the residue was diluted with EtOAc. The organic layer was washed with 1 M HCl, dried over MgSO4, filtered and concentrated to yield the desired product (200 mg, 102%) as a light yellow solid. LCMS Anal. Calc'd for C17H20N2O3 300.15, found [M+H] 301.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([CH3:19])[C:16]([NH2:18])=[NH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21]N>>[CH3:21][NH:17][C:16](=[NH:18])[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:19]
Reactant: CC(C(=N)N)c1ccccc1OCc1ccccc1
Reactant: CN
Agent: Cl
Product: CNC(=N)C(C)c1ccccc1OCc1ccccc1

Procedure:
N-Methyl-2-(2-benzyloxyphenyl)propionamidine was prepared by the method described in Example 88 for the synthesis of 2-(2-benzyloxy-phenyl) propionamidine using methylamine hydrochloride instead of ammonium hydrochloride.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CCNCC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: CCN(CC)CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and Diethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-diethyl-amine, MS: 446 (MH+,1Br).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[CH:3]1.N1C=CN=C1.[CH2:16]([Si:18](Cl)([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:17]>CN(C)C=O.CCOCC>[CH2:8]([C:4]1[C:5](=[O:7])[CH2:6][CH:2]([O:1][Si:18]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:16][CH3:17])[CH:3]=1)[C:9]#[CH:10]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C#CCC1=CC(O)CC1=O
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC1=CC(O[Si](CC)(CC)CC)CC1=O
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.84 mmole) of the title compound of Example 2 in 4 ml of dimethylformamide was treated successively with 200 mg (3 mmole) of imidazole and 300 mg (2 mmole) of triethylsilyl chloride. After stirring for thirty minutes, the reaction mixture was diluted with ether, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness. The crude material was chromatographed on silica gel to give 0.37 g of the title compound as an oil. Structure assignment was confirmed by the proton nmr spectrum: 2.13 (t, J=2 Hz, ≡C--H), 3.08 (mult, --CH2 --C≡), 4.90 (mult, C-11), ##STR7##
Reaction SMILES: C1(C[C:8]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][C:18]=2[F:26])(C([O-])=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=1[F:26])[CH3:13]
Reactant: CCOC(=O)C(Cc1ccccc1)(C(=O)[O-])c1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1F
Yield: 60.3 %

Procedure:
Ethyl phenylmethyl(2-fluoro-4-nitrophenyl)propanedioate (3.86 g, 10.6 mmol) dissolved in ethanol, was treated with ammonium formate (6.7 g, 10.6 mmol) and palladium on carbon 10% paste (380 mg) was added under argon. The reaction mixture was refluxed for 3 hours, cooled and filtered. Evaporated and purified by chromatography on silica gel eluting with ethyl acetate/hexane (1:1) to give the title compound as a yellow oil (1.26 g). LC/MS: Rt=2.10, [MH]+ 198.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([C:13](O)=O)[C@@H:11]([CH3:16])[O:10]C1(C)C)=O)(C)(C)C.[NH2:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH:23]=[CH:24][C:25]=1[NH2:26]>>[NH2:8][C@@H:12]([C:13]1[NH:26][C:25]2[CH:24]=[CH:23][C:22]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[CH:21][C:20]=2[N:19]=1)[C@H:11]([OH:10])[CH3:16]
Reactant: N#Cc1ccc(-c2ccc(N)c(N)c2)cc1
Reactant: C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C(=O)O
Product: C[C@@H](O)[C@@H](N)c1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using (4R,5R)-3-(tert-butoxycarbonyl)-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (Preparation 59A) and 3′,4′-diaminobiphenyl-4-carbonitrile (Preparation 82). The reaction mixture was concentrated in vacuo and purified by SCX-2 cartridge (16 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([S:17][CH3:18])[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)=[O:4]>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][C:3]([C:5]1([S:17][CH3:18])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(SC)CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(SC)CCNC1
Reaction time: 2 h
Yield: 217.2 %

Procedure:
3-Methylsulfanyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2.15 gm, 8.8 mmol) was dissolved in 20 ml of 50% trifluoroacetic acid/dichloromethane and stirred for 2 hrs. The reaction mixture was evaporated to give 3.35 g of 3-Methylsulfanyl-pyrrolidine-3-carboxylic acid methyl ester 4BP as a gummy solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[NH:20][CH2:21][CH2:22][C:17]=2[CH:16]=1>>[Br:14][C:15]1[S:24][C:18]2[CH:19]([CH3:23])[N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH2:21][CH2:22][C:17]=2[CH:16]=1
Reactant: CC1NCCc2cc(Br)sc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2sc(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 2-bromo-7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][F:20])[C:5]2=[CH:6][N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:16][CH2:17][CH2:18][CH2:19][F:20])[C:5]2=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cc2cc(Cl)ncc2n1CCCCF
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1cc2cc(Cl)ncc2n1CCCCF
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To a solution of ethyl 5-chloro-1-(4-fluorobutyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxylate 10-c (2.19 g, 7.3 mmoles) in THF (150 mL) was added lithium aluminium hydride (8.064 mL, 1.1 eq, 1M in THF) at −75° C. under a nitrogen atmosphere. The reaction was allowed to stir on the cooling bath for two hours while it was slowly warming up until 0° C. Then the mixture was cooled on an ice ethanol bath and carefully decomposed by adding 150 mL ethylacetate followed by 10 g of Na2SO4.10H2O. The mixture was stirred for one hour and then dried over MgSO4, filtered off and the filtrate was evaporated. The residue was purified over silica with dichloromethane/methanol 95/5 as eluent to give 550 mg (30% yield) of the targeted compound 10. m/z=257 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]2[C:4](=[C:5]([Cl:13])[C:6]([Cl:12])=[C:7]([OH:11])[CH:8]=2)[C:3]1=[O:14].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].O>CN(C)C=O>[O:14]=[C:3]1[C:4]2[C:9](=[CH:8][C:7]([O:11][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:6]([Cl:12])[C:5]=2[Cl:13])[CH2:10][C:2]1([CH3:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(c2ccccc2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methyl-2-phenyl-5-hydroxy-6,7-dichloro-1-indanone (9.2 g., 0.03 mole), potassium carbonate (8.29 g., 0.06 mole) and tert-butyl bromoacetate (6.44 g., 0.033 mole) in dimethylformamide (30 ml.) is stirred at 25° C. for two hours. The reaction mixture is poured into cold water (150 ml.) and the tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.
Reaction SMILES: C[Mg]Br.[C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])(=[O:6])[CH3:5].OS(O)(=O)=O.[C:35]([O-])(O)=O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:11]([CH:21]=1)[C:12]([NH:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:35])[CH3:5]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reactant: O=C([O-])O
Agent: C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 0.75 h

Procedure:
3M Methylmagnesium bromide (0.10 ml, 0.29 mmol) was added to a solution of 5-acetyl-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 72; 100 mg, 0.29 mmol) in tetrahydrofuran (3 ml) at 0° C. The solution was stirred for 45 minutes. Another 3 equivalents of 3M methylmagnesium bromide (300 ul) were added at 0° C. and solution was stirred for 18 hours. 1N H2SO4 (5 ml) was then added, the mixture was stirred for 3 minutes, then ethyl acetate (10 ml) was added. The acid layer was basified to pH 9 using saturated NaHCO3 solution. The organic layer was washed with saturated NaHCO3 solution (5 ml), dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by MDAP to give the title compound as a white solid. 61 mg.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][C:8]=1[Cl:22])[CH3:6])=[O:4].[C:23]([O:27][C:28](=[O:45])[CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.O>[C:23]([O:27][C:28](=[O:45])[CH2:29][N:30]([CH2:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:2][C:3]([N:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][C:8]=1[Cl:22])[CH3:6])=[O:4])([CH3:24])([CH3:25])[CH3:26]
Reactant: CN(C(=O)CCl)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Reactant: CC(C)(C)OC(=O)CNCc1cccc(C(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)CN(CC(=O)OC(C)(C)C)Cc1cccc(C(=O)OC(C)(C)C)c1)c1ccc(OCOCC[Si](C)(C)C)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)-N-methylacetamide (500 mg) in acetonitrile (8.95 mL) were added tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}benzoate (441 mg), potassium carbonate (285 mg), and potassium iodide (22.8 mg), followed by stirring at 60° C. overnight. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 3-{[(2-tert-butoxy-2-oxoethyl){2-[(2-chloro-4-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)(methyl)amino]-2-oxoethyl}amino]methyl}benzoate (809 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].C([O:23][C:24]1[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30][NH2:31])=O)=[CH:26][C:25]=1[CH2:35][CH3:36])C1C=CC=CC=1>>[CH2:35]([C:25]1[CH:26]=[C:27]([C:28]2[O:13][C:11]([C:9]3[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=3)=[N:31][N:30]=2)[CH:32]=[C:33]([CH3:34])[C:24]=1[OH:23])[CH3:36]
Reactant: COc1cc(CC(C)C)nc(C(=O)O)c1
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Product: CCc1cc(-c2nnc(-c3cc(OC)cc(CC(C)C)n3)o2)cc(C)c1O

Procedure:
The title compound is prepared in analogy to Example 18 starting from 6-isobutyl-4-methoxy-pyridine-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide; LC-MS: tR=1.04 min, [M+H]+=368.33.