Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH:7]=O)[C:3]([O:5][CH3:6])=[O:4].[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:18]3=[CH:27][C:28]([S:30][CH3:31])=[CH:29][N:17]3[CH2:16][C:15]=2[CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:7][C:2]([CH3:1])([CH3:9])[C:3]([O:5][CH3:6])=[O:4])[CH2:23][CH2:22]3)[C:18]3=[CH:27][C:28]([S:30][CH3:31])=[CH:29][N:17]3[CH2:16][C:15]=2[CH:32]=1
Reactant: CSc1cc2n(c1)Cc1cc(Cl)ccc1N=C2N1CCNCC1
Reactant: COC(=O)C(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)CN1CCN(C2=Nc3ccc(Cl)cc3Cn3cc(SC)cc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
Add methyl 2,2-dimethyl-3-oxo-propanoate (0.928 g, 7.13 mmoles) in DCM (5 mL) to 7-chloro-2-(methylsulfanyl)-11-(piperazin-1-yl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine (1.0 g, 2.85 mmoles) in DCM (10 mL) and stir under nitrogen for 30 minutes at room temperature. Add sodium triacetoxyborohydride (3 equiv; 1.89 g, 8.56 mmoles) to the reaction mixture and stir under nitrogen overnight at room temperature. Add methanol and apply to an SCX-2 column, wash with methanol and elute with 2M ammonia in methanol. Evaporate the methanol solution to give methyl 3-[4-(7-chloro-2-(methylsulfanyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-yl)piperazin-1-yl]-2,2-dimethylpropanoate (1.23 g, 84%). MS (m/z): 461.12 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[CH:5][NH:4][N:3]=1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11]>C1COCC1.CCOC(C)=O>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:6]1[C:2]([CH3:1])=[N:3][NH:4][CH:5]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cc1n[nH]cc1C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1n[nH]cc1/C=N/[S@](=O)C(C)(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 57.2 %

Procedure:
3-methyl-1H-pyrazole-4-carbaldehyde (2.03 g, 18.44 mmol) was dissolved in THF (30 ml) and (R)-2-methylpropane-2-sulfinamide (2.35, 19.39 mmol) was added followed by Ti(OEt)4 (8.41 mmol, 36.90 mmol). The resulting reaction mixture was stirred at 80° C. for 18 h. LCMS shows mostly product. The reaction mixture was diluted with EtOAc (300 mL), washed with 4% aqueous NaCl (2×150, 2×50 mL). The combined aq. layers were back extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. Purified by column chromatography (REDI 80 g, EtOAc/heptane 20-100% over 33 min 100% for 7 min.) to give title compound (2.25 g, 10.55 mmol).
Reaction SMILES: BrC1C(OC)=C(C(C[S:14]([C:17]2[CH:22]=[CH:21][C:20](F)=[CH:19][CH:18]=2)(=[O:16])=[O:15])=CC=1)C(OCC)=O.Br[CH2:27][C:28]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:32]([O:39][CH3:40])[C:31]([I:41])=[C:30]([O:42][CH3:43])[CH:29]=1>>[C:17]1([S:14]([CH2:27][C:28]2[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:32]([O:39][CH3:40])[C:31]([I:41])=[C:30]([O:42][CH3:43])[CH:29]=2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CBr)cc(OC)c(I)c1OC
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)cc(OC)c(I)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 85, starting from ethyl 6-bromomethyl-3-iodo-2,4-dimethoxybenzoate (Intermediate 202).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([CH2:19]OS(C)(=O)=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([CH2:19][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Cn2cccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 17.9 mg (0.26 mmol) pyrazole in 2 mL dry THF at 0° C. was added 14 mg (0.35 mmol, 60% dispersion in mineral oil) NaH and the reaction was stirred for 30 minutes. 50 mg (0.17 mmol) 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 1 mL dry THF was added dropwise and the reaction was allowed to warm to room temperature for 16 hours. The solvent was evaporated and the remaining residue was partitioned between 25 mL H2O and 25 mL EtOAc. The organic phase was washed with 25 mL 1% citric acid solution, H2O (3×25 mL), 25 mL brine and dried with Na2SO4. After filtration and evaporation of the solvent the product was used in the next step without further purification.
Reaction SMILES: C(C[C@@H:4]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:5]1[CH2:6][O:7][CH2:8]2)#N.[C:19]([OH:22])(=[O:21])[CH3:20]>Cl>[CH:9]12[NH:11][CH:5]([C@H:4]([CH2:20][C:19]([OH:22])=[O:21])[CH2:10]1)[CH2:6][O:7][CH2:8]2
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1C2COCC1[C@H](CC#N)C2
Agent: Cl
Product: O=C(O)C[C@@H]1CC2COCC1N2
Yield: 99 %

Procedure:
A solution of tert-butyl (6S)-6-(cyanomethyl)-3-oxa-8-azabicyclo[3.2.1]octane-8-carboxylate 64b (180 mg, 0.71 mmol) in Conc. HCl (5 mL) and acetic acid (1 mL) was stirred at 100° C. for 4 h. Then the mixture concentrated in vacuo to afford 2-[(6S)-3-oxa-8-azabicyclo[3.2.1]octan-6-yl]acetic acid 64c (121 mg, 99%) which was used for next step without further purification. MS: calc'd (MH+) 172, measured (MH+) 172.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[CH2:29]([O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[N+:46]([O-:48])=[O:47])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl.O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:37]([O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:38]([N+:46]([O-:48])=[O:47])[CH:39]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)c2ccc(OCc3ccccc3)c([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-amino-benzoic acid ethyl ester (17 g, 103 mmol) in dichloromethane (500 mL) and triethylamine (20.8 g, 28.5 mL, 206 mmol) was treated with dimethylaminopyridine (0.63 g, 5 mmol) and 4-benzyloxy-3-nitro-benzoyl chloride (30 g, 103 mmol). The mixture was stirred at room temperature overnight, while a thick white precipitate formed. The slurry was diluted with water (10 mL) and stirred vigorously, then filtered, washing with dichloromethane and water. The solid was dried under high vacuum to yield 4-(4-benzyloxy-3-nitro-benzoylamino)benzoic acid ethyl ester as a white solid, 26.5 g (61%), MS (ISP): m/e=419.3 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33](=[O:37])[N:32]([CH:38]1[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]1=[O:45])[CH2:31]2.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:26][CH2:27][C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[C:33](=[O:37])[N:32]([CH:38]2[CH2:43][CH2:42][C:41](=[O:44])[NH:40][C:39]2=[O:45])[CH2:31]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc(Cl)c(Cl)c1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 34.8 %

Procedure:
A mixture of 3,4-dichlorophenyl-acetic acid (0.31 g, 1.5 mmol) and CDI (0.26 g, 1.6 mmol) in DMF (20 mL) was stirred at 70° C. under N2. After 4 h, 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (0.47 g, 1.5 mmol) was added. The mixture was cooled to 40° C. and was stirred at this temperature for an additional 16 h. Water (30 mL) was added resulting in precipitation of the product. The solid precipitate was filtered, washed with water (50 mL) and dried in vacuo providing 2-(3,4-dichloro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-acetamide as a yellow solid (0.24 g, 34% yield); mp 191-193° C.; HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.17 (98.19%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.32-2.45 (m, 1H), 2.57-2.73 (m, 1H), 2.86-2.98 (m, 1H), 3.54 (s, 2H), 4.45-5.14 (m, 4H), 5.11 (dd, 1H, J=13.2, J=5.1), 7.24 (dd, 1H, J=8.4, J=6.3), 7.29-7.47 (m, 2H), 7.48-7.59 (m, 2H), 7.67 (d, 1H, J=7.8), 8.72 (t, 1H, J=5.7), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 41.0, 42.3, 47.1, 51.6, 122.1, 123.0, 127.1, 129.1, 129.5, 130.3, 130.4, 130.6, 131.1, 137.3, 142.3, 143.6, 168.0, 169.4, 170.9, 172.8; LCMS: MH=461, 463; Anal. Calcd for C22H19Cl2N3O4+0.5H2O: C, 56.30; H, 4.30; N, 8.95. Found: C, 56.19; H, 3.91; N, 8.56.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]#[C:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][OH:17])=[C:11](/[CH:30]=[CH:31]/[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=[C:9]1[C:37]([O:39]CC1C=CC=CC=1)=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.CO>O.[OH-].[OH-].[Pd+2]>[CH2:1]([N:8]1[C:12]([CH2:13][CH2:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:16][OH:17])=[C:11]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:10]=[C:9]1[C:37]([OH:39])=[O:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cc(C(=O)OCc2ccccc2)n(Cc2ccccc2)c1C#CC(CO)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CCOC(=O)CCc1cc(C(=O)O)n(Cc2ccccc2)c1CCC(CO)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 11 h

Procedure:
A 25-mL flask was charged with 6 (21 mg, 0.03 mmol), 20% Pd(OH)2 on carbon (nominally 50% in water, 7 mg), and 1 mL each of EtOAc and MeOH. The suspension was stirred under a hydrogen balloon at room temperature for 5-17 hours. The catalyst was filtered off (Celite), the residue concentrated to give 20 mg (quantitative) of a pale yellow foam, which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.30-7.15 (m, 13H), 6.95 (s, 1H), 6.90 (m, 2H), 5.45 (ABq, J=16.4 Hz, 2H), 4.21 (td, J=8.5, 2.1 Hz, 1H), 4.09 (q, J=7.0H, 2H), 3.75 (d, J=8.6 Hz, 1H), 2.72-2.58 (m, 4H), 2.46 (t, J=7.4 Hz, 2H), 1.06-1.51 (m, 2H), 1.48-1.44 (m, 2H), and 1.22 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.45, 165.67, 142.18, 141.36, 139.65, 138.95, 129.11, 128.99, 128.88, 128.72, 128.30, 127.20, 127.15, 126.94, 126.01, 120.86, 120.09, 119.67, 73.09, 60.66, 58.67, 48.23, 35.37, 34.81, 21.23, 20.70, and 14.50; IR (KBr) 3428, 3027, 2933, 1732, 1663, and 1450 cm−1; LRMS-El m/z 481 ([M−CO2+], 64%), 167 ([Ph2CH3+], 75%), and 91 ([PhCH2+], 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].Cl[CH2:15][CH2:16][CH2:17][S:18](Cl)(=[O:20])=[O:19]>>[O:19]=[S:18]1(=[O:20])[CH2:17][CH2:16][CH2:15][N:1]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)c(OC)c1
Product: COc1cc(C(=O)O)ccc1N1CCCS1(=O)=O

Procedure:
Using methyl 4-amino-3-methoxybenzoate (1.22 g) and 3-chloropropane-1-sulfonyl chloride (1.1 mL) and by the reaction and treatment in the same manner as in Preparation Example 16, the title compound (1.05 g) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10]Br)[CH:9]=1)[C:5]#[N:6].[C:12]([O-:23])(=O)[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15]([O-])=[O:16].[K+].[K+].C[N:27](C=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][N:27]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:23])[CH:9]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Br)cc(CBr)c1
Reactant: CN(C)C=O
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Agent: [K+]
Product: N#Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
A suspension of 3-bromo-5-(bromomethyl)benzonitrile (12.5 g, 45.5 mmol), potassium phthalate (7.16 g, 38.6 mmol), and in DMF (100 mL) was stirred under reflux for 4 h. After cooled to room temperature, the solvent was remove under reduced pressure and the residue was dissolved in CHCl3 (200 mL). The organic layer was washed with water (50 mL×2), dried over Na2SO4, and concentrated in vacuum to obtain 15.2 g of the crude product. The product, 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 23%) was purified by flash column chromatography. 1H NMR (400 MHz, CDCl3): δ 7.90-7.87 (m, 2 H), 7.81-7.80 (m, 1 H), 7.77-7.75 (m, 2 H), 7.71-7.70 (m, 1 H), 7.66-7.65 (m, 1 H), 4.83 (s, 2 H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:76][N:77]([CH3:82])[CH2:78][CH2:79][CH2:80][NH2:81]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([F:31])=[CH:29][C:25]([C:26]([NH:81][CH2:80][CH2:79][CH2:78][N:77]([CH3:82])[CH3:76])=[O:28])=[C:24]([F:32])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CCCN
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3cc(F)c(C(=O)O)cc3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCCNC(=O)c1cc(F)c(Nc2ncc3c(n2)N(C2CCCC2)CC(F)(F)C(=O)N3C)cc1F
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a mixture of 0.0606 g (0.134 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,5-difluoro-benzoic acid (I-232) and 4 mL of dimethylformamide was added 0.0292 g (0.216 mmole) of 1-hydroxybenzotriazole, 0.0784 g (0.207 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.1083 g (0.804 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0202 g (0.198 mmole) of 3-(dimethylamino)-propylamine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0576 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-2,5-difluoro-benzamide (I-237) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH:25]=[C:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1.N1C=C(C(O)=O)C=C(C(O)=O)C=1.C1(C)C=C(C)C=C(C)C=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:19]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=C2SC(=O)NC2=O)c2sccc12
Agent: O=C(O)c1cncc(C(=O)O)c1
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CC2SC(=O)NC2=O)c2sccc12
Temperature: 167 °C
Yield: 92.9 %

Procedure:
A 100 ml, 4-necked glass flask equipped with a mechanical stirrer, a thermometer, a cooler, a dropping funnel and an argon inlet was charged under argon in sequence with 9.20 g (19.6 mmol) of 5-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzo[b]thien-7-yl]methylene]-2,4-thiazolidinedione, 7.84 g (29.4 mmol) of 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-, diethyl ester and 43 ml of mesitylene. The suspension was stirred at reflux (ca. 167° C.) for 6 h, then the heating bath was removed. When the resulting suspension had a temperature of ca. 85° C. 125 ml of ethanol were added. After 2 h stirring at room temperature the precipitate was isolated by filtration, the filter cake was washed with 50 ml of ethanol and dried at 56° C./1 mbar for 2 h to afford 8.46 g (92%) of 5-{[4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl]methyl}-2,4-thiazolidinedione as off-white crystalline material, which according to HPLC analysis had 99.3% purity.
Reaction SMILES: Br[C:2]1[C:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.[Li]CCCC.[C:26](=[O:28])=[O:27]>O1CCCC1>[CH2:15]([C:3]1[C:2]([C:26]([OH:28])=[O:27])=[CH:14][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:13])([CH3:12])[C:5]=2[CH:4]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCc1cc2c(cc1Br)CCCCC2(C)C
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCc1cc2c(cc1C(=O)O)CCCCC2(C)C
Reaction time: 0.67 h

Procedure:
This 3.21 g of 2-bromo-3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene were placed in 30 ml of abs. tetrahydrofuran under Ar and treated at -78° with 6.75 ml of 1.55M nBuLi (hexane) (1.1 eq.). The metal/halogen exchange was followed by gas chromatography (GC). After 40 min., a large excess of CO2 gas was introduced and the cooling bath was removed. After 10 min., the mixture was poured on to ice/NH4Cl solution, extracted with diethyl ether, washed with H2O, dried over Na2SO4 and the solvent was removed in a vacuum. Flash chromatography on SiO2 (hexane/ethyl acetate=8/2) yielded 2.26 g of 3-hexyl-5,5-dimethyl-6,7,8,9-tetrahydro-5H-benzocycloheptene-2-carboxylic acid as white crystals of m.p. 74°-75°.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]([C@@H:23]([CH3:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH2:20][CH2:21][CH3:22])[C:10](=[O:36])[CH2:9]1)=O)(C)(C)C.[ClH:37].C(=O)([O-])[O-].[Na+].[Na+]>>[ClH:37].[ClH:37].[CH3:34][S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@@H:23]([N:19]([CH2:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][C:10]2=[O:36])[CH3:35])=[CH:26][CH:27]=1)(=[O:32])=[O:33]
Reactant: CCCN(CCCCN1CCCN(C(=O)OC(C)(C)C)CC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN(CCCCN1CCCNCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4-{[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamino}butyl)-3-oxo-[1,4]diazepane-1-carboxylic acid tert-butyl ester (0.9 g, 1.75 mmole) and 3N hydrochloric acid (4 mL) was warmed to 50° C. The reaction mixture was stirred at room temperature for 30 minutes, and the pH was adjusted to 10 with saturated sodium carbonate. The mixture was extracted with ethyl acetate (30 mL), and the organic phase was dried (magnesium sulfate), and concentrated. The residue was dissolved in diethyl ether (10 mL) and 1 M hydrogen chloride in diethyl ether (2 mL) was added. The precipitate was collected, washed with diethyl ether and hexane, and dried in vacuo to give 1-(4-{[(S)-2-(-4-methanesulfonyl-phenyl)-1-methylethyl]propylamino}butyl)-[1,4]diazepan-2-one, dihydrochloride salt (0.49 g),149, M+H=424.
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.B(F)(F)F.[O:31]1CC[CH2:33][CH2:32]1>>[O:1]1[C:3]2([CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:2][O:31][CH2:32][CH2:33]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C1CCOC1
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)COCCO4)c(F)c2)C(=O)O1
Yield: 44 %

Procedure:
A mixture of (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.275 mmol) ethylene glycol (0.330 mmol) and Catalytic amount of BF3.etharate in 10 ml tetrahydrofuran was stirred under reflux for 2 hours. The reaction mixture was evaporated to the dryness under vacuum. The residue obtained was purified on the silica gel column chromatography to provide title compound in 44% yield.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:23][C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=2)=[N:28][CH:29]=1>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:23][C:24]2[CH:29]=[N:28][C:27]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([Cl:38])[CH:32]=3)=[N:26][CH:25]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(O)cc1
Reactant: ClCc1cnc(Nc2ccc(Cl)c(Cl)c2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(OCc2cnc(Nc3ccc(Cl)c(Cl)c3)nc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A mixture of 4-((tert-butyldimethylsilyl)oxy)phenol (0.086 g, 0.381 mmol), Cs2CO3 (0.186 g, 0.572 mmol) and 5-(chloromethyl)-N-(3,4-dichlorophenyl)pyrimidin-2-amine (0.110 g, 0.381 mmol) in DMF (3.8 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by flash chromatography on silica gel using 10-50% ethyl acetate in hexanes. The desired fractions were concentrated to give 5-((4-(tert-butyldimethylsilyloxy)phenoxy)methyl)-N-(3,4-dichlorophenyl)pyrimidin-2-amine as a yellow solid (0.022 g, 12%). LCMS: R.T.=3.73 min; [M+H]+=476.23
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.C1COCC1.[BH4-].[Na+]>O>[OH:3][CH:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([O:10][CH2:11][CH:12]=[CH2:13])=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C=CCOC(=O)c1ccc(C(C)=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOC(=O)c1ccc(C(C)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.1 g (15 mmol) of the allyl ester obtained above in (a), 20 ml of methyl alcohol and 20 ml of THF are introduced into a round-bottomed flask. While cooling in an icebath, 285 mg (7.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for one hour. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. 3.1 g (100% ) of the expected product are collected in the form of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.CC1ON=C(C2C=CC=CC=2)C=1COC1C=CC(C(O)=O)=CN=1.[NH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Agent: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 30 %

Procedure:
As described for example 191, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid, using 2-amino-2-methyl-1-propanol instead of 2-aminoethyl isopropylether, to the title compound (37 mg, 30%) which was obtained as a white solid. MS: m/e=416.2 [M+H]+.