Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38]([OH:40])=O)[NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][C:63]([P:66](=[O:73])([O:70]CC)[O:67]CC)([F:65])[F:64]>>[NH2:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38](=[O:40])[NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][C:63]([P:66](=[O:67])([OH:73])[OH:70])([F:64])[F:65]
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCN
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: Cl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCOCCC(F)(F)P(=O)(O)O)OC(=O)CCCCCCCCCCC

Procedure:
The title product was prepared from (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) and diethyl 3-(2-aminoethoxy)-1,1-difluoropropylphosphonate hydrochloride (1.2 eq) by following the procedure described for example 19, step 4-6. 1H NMR (CDCl3): δ 8.08 (br s, 1H), 5.11-5.24 (m, 1H), 4.31 (dd, 1H), 4.08-4.25 (m, 2H), 3.64-3.80 (m, 3H), 3.48-3.64 (m, 2H), 2.99-3.19 (m, 3H), 2.82 (dd, 1H), 2.72 (dd, 1H), 2.23-2.37 (m, 6H), 1.51-1.64 (m, 4H), 1.16-1.36 (m, 32H), 0.88 (t, 6H). LRMS [M+H]=761.4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(OCc2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of 4-(3,4-difluorobenzyloxy)phenol (1.00 g, 4.2 mmol) in N,N-dimethylformamide (20 ml) was added potassium tert-butoxide (0.47 g, 4.2 mmol), followed by stirring at room temperature for 30 minutes. To the reaction solution was added 1-fluoro-2-nitrobenzene (0.60 g, 4.3 mmol), followed by stirring at 150° C. for 5 hours. After allowing to stand overnight, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform) to give 1-[4-(3,4-difluorobenzyloxy)phenoxy]-2-nitrobenzene (1.41 g).
Reaction SMILES: [N+:1]([CH:4]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:5](=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-])=O.Cl.[N:24]#[C:25][NH2:26]>[Pd]>[CH2:18]([C:4]1[NH:1][C:25]([NH2:26])=[N:24][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(C(=O)CCCCCc1ccccc1)[N+](=O)[O-]
Reactant: N#CN
Agent: [Pd]
Agent: Cl
Product: CCCCCc1[nH]c(N)nc1CCCCCc1ccccc1

Procedure:
7-Nitro-1-phenyldodecan-6-one (0.090 g, 0.29 mmol) reacted with concentrated HCl (1.45 mmol) and palladium, 5 wt. % on activated carbon (0.125 g, 0.060 mmol) under H2, then reacted with cyanamide (0.062 g, 1.47 mmol) according to the general procedure. Purification by column chromatography gave 0.071 g (81%) over two steps as a yellow oil: 1H NMR (300 MHz, CD3OD) δ 7.20 (m, 2H), 7.14 (m, 3H), 2.59 (t, J=7.5 Hz, 2H), 2.42 (m, 4H), 1.56 (m, 6H), 1.32 (m, 6H), 0.90 (t, J=7.2 Hz, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 146.3, 142.5, 128.3, 128.1, 125.6, 122.1, 121.8, 35.5, 31.1, 31.1, 28.7, 28.7, 28.2, 23.1, 23.0, 22.3, 13.3 ppm; IR νmax (cm−1) 3169, 2928, 2857, 1680, 1453, 1202, 1030, 746, 699; HRMS (FAB) calcd for C19H29N3 (MH+) 300.2434, found 300.2441.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:15][C:2]2[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=2)=[CH:12][CH:11]=1
Reactant: OCc1ccc(F)cc1
Reactant: CSc1nsc(Cl)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 3 ml of N,N-dimethylformamide were dissolved 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 4-fluorobenzyl alcohol, 84 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 357 mg of 5-(4-fluorobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (12)).
Reaction SMILES: [H-].[Na+].[CH:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]1(/[C:14](/[CH2:21][C:22](OCC)=[O:23])=[CH:15]\[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[OH:23][CH:22]=[C:21](/[C:14](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC=O
Reactant: CCOC(=O)/C=C(/CC(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)/C=C(/C(=CO)C(=O)OCC)c1ccccc1
Yield: 97 %

Procedure:
A stirred mixture of NaH (158.4 mg, 6.6 mmol) and ethyl formate (1.07 ml, 13.2 mmol) in Et2O (5 ml) were refluxed under argon for 15 min. Diethyl (2Z)-3-phenylpent-2-ene-1,5-dioate in Et2O (5 ml) was added dropwise to the above solution over 5 min at rt. The reaction was heated to reflux for 12 hours. The heterogeneous yellow mixture was diluted with Et2O (100 ml), washed with sat. NH4Cl (40 ml), half sat. NH4Cl (40 ml), brine (20 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The product diethyl (3E)-2-(hydroxymethylene)-3-phenylpent-3-ene-1,5-dioate was obtained in 97% yield and could be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:10]=[CH:11][C:12]([N:15]([S:34]([CH3:33])(=[O:36])=[O:35])[S:34]([CH3:33])(=[O:36])=[O:35])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:16][C:17](=[O:25])[C:18]([O:21][C:22](=[O:24])[CH3:23])([CH3:20])[CH3:19]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N)cc2)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC(C)(C)C(=O)Nc1ccc(Sc2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)cc1Cl
Temperature: 2.5 °C
Reaction time: 0.05 h

Procedure:
N-[2-Chloro-4-(4-aminophenylsulphanyl)phenyl]-2-acetoxy-2-methylpropanamide (Method 22) (0.50 g) was dissolved in DCM (10 m) and cooled to 0-5° C. in an ice bath. Triethylamine (0.55 ml) was added followed by dropwise addition of methylsulphonyl chloride (0.11 ml) and the mixture was allowed to warm to ambient temperature over 2 hours. The solution was concentrated then the solid was dissolved in DCM (5 ml) and water (5 ml) was added. The solution was loaded onto a Varian Chem Elut column and after 3 minutes was washed through with DCM (20 ml). The DCM layer was then concentrated and the solid washed with ether and filtered to give the title compound (0.58 g) as a solid. NMR (CDCl3): 1.7 (s, 6H), 2.2 (s, 3H), 3.4 (s, 6H), 7.2 (s, 4H), 7.4 (d, 1H), 7.5 (d, 1H), 8.4 (d, 1H), 8.5 (d, 1H); MS (ESP−): 533; EA: found: C, 44.4; H, 4.5; N, 5.1%; C20H23ClN2O7S3 requires C, 44.9; H, 4.3; N, 5.2%.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1.[F:42][C:43]1[CH:56]=[CH:55][C:46]([O:47][C:48]2[CH:49]=[C:50]([NH2:54])[CH:51]=[CH:52][CH:53]=2)=[CH:45][CH:44]=1>C(OCC)(=O)C.CN(C)C=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:54][C:50]2[CH:51]=[CH:52][CH:53]=[C:48]([O:47][C:46]3[CH:55]=[CH:56][C:43]([F:42])=[CH:44][CH:45]=3)[CH:49]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: Nc1cccc(Oc2ccc(F)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(Oc3ccc(F)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
To a mixture of N-Boc piperidine-4-carboxylic acid (9.2 g, 0.04 mol) and DCC (dicyclohexylcarbodiimide) (8.2 g, 0.04 mol) in ethyl acetate (150 mL) was added HOAt (1-hydroxy-7-azabenzotriazole) (5.5 g, 0.04 mol) in DMF (dimethylformamide) (40 mL). The mixture was stirred at room temperature for 10 minutes and then 3-(4-fluoro-phenoxy)-phenylamine (8.7 g, 0.043 mol) in ethyl acetate (50 mL) was added. The reaction mixture was allowed to stir overnight at room temperature and then was concentrated to remove most of the ethyl acetate. The precipitated solid was removed by filtration through Celite. The filtrate was diluted with ethyl acetate and washed with 1 N HCl, saturated NaHCO3 and brine (3×60 mL). The organic phase was dried with MgSO4 and concentrated. The residue was purified on silica eluting with 20% ethyl acetate/hexanes to afford 4-[3-(4-fluoro-phenoxy)-phenylcarbamoyl]-piperidine-1-carboxylic acid tert-butyl ester (14.2 g, 86%) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[NH:6][N:5]=1)(=[O:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[CH:24]=[CH:23][N:22]([CH2:25][C@@H:26]([NH2:28])[CH3:27])[N:21]=2)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:28][C@@H:26]([CH3:27])[CH2:25][N:22]2[CH:23]=[CH:24][C:20]([C:15]3[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=3)=[N:21]2)=[O:11])[NH:6][N:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(Cl)c(Cl)c3)n2)[nH]n1
Yield: 12.61 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 3-acetyl-1H-pyrazole-5-carboxylic acid (71.9 mg, 0.466 mmol) and (S)-1-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)propan-2-amine (126 mg, 0.466 mmol). The product was purified by recrystallization from acetonitrile. Yield 12.61%. 1H-NMR (400 MHz; DMSO-d6): δ 1.05-1.25 (m, 3H), 4.18-4.53 (m, 3H), 6.79 (s, 1H), 7.31 (s, 1H), 7.57-7.85 (m, 3H), 7.89-7.98 (m, 1H), 8.39-8.54 (m, 1H), 14.05& 14.12 (2 broad s, 1H).
Reaction SMILES: [C:1]([C:3](=[C:8]1[CH2:12][C:11]([CH3:14])([CH3:13])[CH2:10][CH:9]1[CH3:15])C(OC)=O)#[N:2].[Cl-].[Li+].CN1CCCC1=O.Cl>O>[CH3:14][C:11]1([CH3:13])[CH2:10][CH:9]([CH3:15])[C:8]([CH2:3][C:1]#[N:2])=[CH:12]1
Reactant: COC(=O)C(C#N)=C1CC(C)(C)CC1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC1CC(C)(C)C=C1CC#N
Temperature: 150 °C
Reaction time: 3 h

Procedure:
The methyl 2-cyano-2-(2,4,4-trimethylcyclopentylidene)acetate B is placed in a round-bottomed flask with 2 eq. of lithium chloride in a 98:2 mixture of NMP (N-methylpyrrolidone) and water. The mixture is stirred at 150° C. After 3 hours, the reaction medium is cooled to ambient temperature before being poured onto a 1% HCl solution. Stirring is carried out for a few minutes and then extraction is carried out twice with MTBE (methyl tert-butyl ether). The combined organic phases are washed with a sodium bicarbonate solution and then with an aqueous sodium chloride solution. After drying over magnesium sulfate, filtering through paper and evaporating the solvent, the crude product is distilled under reduced pressure. A 70:30 mixture of 2-(2,4,4-trimethylcyclopent-1-enyl)acetonitrile and 2-(3,3,5-trimethylcyclopent-1-enyl)-acetonitrile is obtained.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[Br:20][C:21]1[O:22][CH:23]=[C:24]([C:26](O)=[O:27])[N:25]=1>>[Br:20][C:21]1[O:22][CH:23]=[C:24]([C:26]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=3[CH3:18])=[N:5]2)=[O:27])[N:25]=1
Reactant: O=C(O)c1coc(Br)n1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3coc(Br)n3)n2)ccc(C#N)c1Cl
Yield: 6.2 %

Procedure:
(S)-2-bromo-N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)-propan-2-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from ((S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (742 mg, 2.70 mmol) and 2-bromooxazole-4-carboxylic acid (492 mg, 2.56 mmol). The product was purified by Flash-chromatography. Yield 6.2%. m/z [448.7+1].
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)=[N:18][N:17]=2)=[CH:12][CH:11]=1.O[N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N:31]1([O:26][C:25](=[O:27])[C:24]2[CH:23]=[CH:22][C:21]([C:19]3[S:20][C:16]([C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:14]=4)=[N:17][N:18]=3)=[CH:29][CH:28]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[N:32]1
Reactant: On1nnc2ccccc21
Reactant: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)O)cc3)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCCCCCOc1ccc(-c2nnc(-c3ccc(C(=O)On4nnc5ccccc54)cc3)s2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
A mixture of 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazole-2-yl]benzoic acid (50 g), 1-hydroxybenzotriazole (18 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide, hydrochloride (34.86 g) in methylene chloride (1 L) was stirred for 16 hours at room temperature then evaportated under reduced pressure and dried for 1 hour under hi-vacuum. Water (1 L) was added to the residue and the resulting precipitate collected by filtration, washed with water (1 L×5), acetonitrile (1L×5), isopropyl ether (250 ml×2), then dried under hi-vacuum to give 4-[5-[4-(6-methoxy-n-hexyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoic acid benzotriazol-1-yl ester (56.92 g) as a yellow powder.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:15])[C:13]2[C:8](=[CH:9][C:10]([Br:14])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C[Si](C)(C)[O-].[K+].O>C1COCC1>[Br:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[C:5]([CH3:15])([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2
Reactant: COC(=O)C1(C)CCc2cc(Br)ccc21
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCc2cc(Br)ccc21
Temperature: 25 °C

Procedure:
A solution of (rac)-5-bromo-1-methyl-indan-1-carboxylic acid methyl ester (1.318 g, 4.9 mmol) and potassium trimethylsilanolate (3.14 g, 24.5 mmol) in dry THF (25 ml) was stirred at reflux for 1 h. The reaction mixture was allowed to cool to room temperature, water was added and the mixture was extracted two times with tert-butyl methylether. The pH of the aqueous layer was carefully adjusted to 3 by addition of 1N HCl and the aqueous layer was extracted two times with EtOAc. The combined EtOAc-layers were washed with brine, dried with Na2SO4 and evaporated. Toluene was added to the remaining residue and it was evaporated to remove water. The title compound was obtained as light yellow solid (1.204 g, 96%). MS: 252.7 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:25][N:26]([CH3:33])[CH2:27]/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:22][CH2:21][CH2:20][N:19]([C:30](=[O:31])/[CH:29]=[CH:28]/[CH2:27][N:26]([CH3:33])[CH3:25])[CH2:18][C:17]=4[S:23][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Reactant: CN(C)C/C=C/C(=O)O
Agent: Cl
Product: CN(C)C/C=C/C(=O)N1CCCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1

Procedure:
The title compound was synthesized in analogy to Example 89 from N-(3-chloro-4-fluorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 81A (160 mg, 80% purity, 0.37 mmol) and (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride from Example 1A (85 mg, 0.51 mmol) to yield 12 mg (7%).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[O:7]=[C:8]([CH3:15])[CH2:9]CCC(O)=O>>[CH3:6][O:5][C:1]([CH2:2][CH2:3][CH2:9][C:8](=[O:7])[CH3:15])=[O:4]
Reactant: CC(=O)CCCC(=O)O
Reactant: C=CC(=O)OC
Product: COC(=O)CCCC(C)=O

Procedure:
Subsequently, the tubes are cooled rapidly, following which the contents of the tubes is analyzed gaschromatographically, and the conversion of the methyl acrylate, as well as the efficiency in the methyl ester of 4-oxopentane-1-carboxylic acid product, referred to the converted methyl acrylate, is determined.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:15]([O-])=O)=[C:5]([CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].CO.[H][H]>[Pd].O1CCCC1>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[CH:12][C:11]([O:13][CH3:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)cc(OC)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(OC)cc(OC)c1N

Procedure:
A mixture of methyl 3,5-dimethoxy-2-nitrobenzoate (Ger 501,609, April 2, 1927; CA. 24, 47929) (39.0 g; 0.162 mole), 5% Pd on charcoal (2.0 g), methanol (200 ml) and tetrahydrofuran (200 ml) is shaken in an atmosphere of hydrogen at 52 lb pressure for 46 h when theoretical amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is recrystallized from methanol. Yield 28.6 g; mp 93°-5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[F:20][C:21]1[C:26]([Cl:27])=[CH:25][C:24]([S:28](Cl)(=[O:30])=[O:29])=[CH:23][CH:22]=1>>[Cl:27][C:26]1[CH:25]=[C:24]([S:28]([N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=2[O:2][CH3:1])[C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=2)(=[O:29])=[O:30])[CH:23]=[CH:22][C:21]=1[F:20]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(CNc2ccc(F)cn2)c(OC)c1
Product: COc1ccc(CN(c2ccc(F)cn2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 18 using N-(2,4-dimethoxybenzyl)-5-fluoropyridin-2-amine (Preparation 20) and 4-fluoro-5-chlorobenzenesulfonyl chloride.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[OH:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH:20]([C:22](OC)=[O:23])[CH2:19][C:18]=3[CH:26]=2)=[CH:10][CH:9]=1)[CH3:7]>CO>[OH:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][CH:20]([C:22]([NH:4][CH2:1][CH:2]=[CH2:3])=[O:23])[CH2:19][C:18]=3[CH:26]=2)=[CH:10][CH:9]=1)[CH3:7]
Reactant: C=CCN
Reactant: COC(=O)C1Cc2cc(-c3ccc(C(C)O)cc3)ccc2O1
Solvent: CO
Product: C=CCNC(=O)C1Cc2cc(-c3ccc(C(C)O)cc3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 ml of 2-propenylamine was added to a mixture of 5.0 g of 6D and 100 ml of methanol. The solution was stirred at room temperature overnight. The volatile materials were evaporated under reduced pressure. The residue was stirred with 50 ml of ether, the solid was collected and dried in a vacuum oven to give 6, mp: 122°-124° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CS(O[CH:13]([CH3:37])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:26][N:25]=2)=[CH:18][CH:17]=1)(=O)=O>CN(C=O)C>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]#[C:22][C:19]3[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([N:5]4[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]4)[CH3:37])=[CH:21][CH:20]=3)=[N:25][CH:26]=2)=[CH:31][CH:32]=1
Reactant: CC1CCNCC1
Reactant: CC(COc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1)OS(C)(=O)=O
Solvent: CN(C)C=O
Product: CC1CCN(C(C)COc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
0.21 mL (1.80 mmol) 4-methylpiperidine are added to a solution of 133 mg (0.30 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-phenoxy}-1-methyl-ethyl methanesulphonate in 2 mL DMF and the mixture is stirred for 16 h at 60° C. and 6 h at 80° C. The solvent is eliminated i.vac., the residue is triturated with isopropanol, suction filtered and dried at 30° C. in the circulating air dryer.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][N:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)C(=O)C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:29][CH2:30]OCC>>[CH2:29]([C:21]1[CH:20]=[C:19]([NH:15][CH2:14][CH2:13][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1)[CH3:30]
Reactant: CCOCC
Reactant: CC(=O)N(CCc1ccccc1)c1ccnc2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCc1cc(NCCc2ccccc2)c2ccccc2n1
Yield: 36.7 %

Procedure:
To a suspension of 0.59 g of lithium aluminum hydride in 100 mL of dry ether was added, dropwise, a solution of 2.3 g of N-(2-phenylethyl)-N-(4-quinolinyl)acetamide dissolved in 50 mL of dry ether. The mixture was heated to reflux for seven hours. Excess lithium aluminum hydride was then destroyed by adding 100 mL of water to the mixture. The solvent was then removed, and the residue was dissolved in chloroform. After washing with water, the mixture was then dried and concentrated. Using HPLC (silica gel, CH2Cl2 →EtOAc), 0.80 g of the title product was isolated. Yield 36.7%. M.P. oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([O:31]CC)=[O:30])[CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[Li+].[OH-]>O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([C:29]([OH:31])=[O:30])[CH:25]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Reaction time: 24 h

Procedure:
A mixture of ethyl 5-(2,4-bis(benzyloxy)-5-chlorophenyl)isoxazole-3-carboxylate (200 mg, 0.43 mmol), methanol (10 ml), water (6-7 ml), and LiOH (16 mg, 0.65 mmol) was allowed to stand at 50-60° C. for 24 h. The solution was concentrated under vacuo to remove methanol, and the remaining aqueous solution was extracted with Et2O to remove traces of unreacted starting material. The aqueous solution was acidified with 1 M HCl and extracted with three portions of AcOEt. The combined organic extracts were washed with saturated aqueous sodium chloride and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded a residue, which was chromatographed on silica gel (DCM/methanol: 9/1).