Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([NH:13][C:14]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=O)[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[O:11][CH3:12].[Si](OC(C)(C)CC1[S:34]C(N)=C(C2C=C(Cl)C=CC=2OC)N=1)(C(C)(C)C)(C)C>>[Cl:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH3:12])=[C:4]([C:3]2[N:13]=[C:14]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[S:34][C:2]=2[NH2:1])[CH:9]=1
Reactant: COc1ccc(Cl)cc1-c1nc(CC(C)(C)O[Si](C)(C)C(C)(C)C)sc1N
Reactant: COc1ccc(Cl)cc1C(NC(=O)C1CCOCC1)C(N)=O
Product: COc1ccc(Cl)cc1-c1nc(C2CCOCC2)sc1N

Procedure:
Using N-(2-amino-1-(5-chloro-2-methoxyphenyl)-2-oxoethyl)tetrahydro-2H-pyran-4-carboxamide, the title compound was prepared following the synthetic procedures described for 2-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-4-(5-chloro-2-methoxyphenyl)thiazol-5-amine to give 4-(5-chloro-2-methoxyphenyl)-2-(tetrahydro-2H-pyran-4-yl)thiazol-5-amine as a white gum. LCMS (ESI) m+H=325.2; 1H NMR (400 MHz, DMSO-d6): δ 7.38 (d, 1H); 7.31 (dd, 1H); 7.09 (d, 1H); 5.31 (s, br, 2H); 3.90 (d, 2H); 3.84 (s, 3H); 3.43 (m, 2H); 3.04-2.99 (m, 1H); 1.90 (d, 2H); 1.66-1.66 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][OH:10].[F:11][C:12]([F:47])([F:46])[C:13]1[CH:14]=[C:15]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17].O>CN(C)C=O>[F:45][C:42]([F:44])([F:43])[C:40]1[CH:39]=[C:15]([CH:14]=[C:13]([C:12]([F:11])([F:46])[F:47])[CH:41]=1)[C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:29]=[N:28][N:27]([CH2:8][CH2:9][OH:10])[CH:26]=2)[CH2:20][C@H:19]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([CH3:38])[CH:32]=1)=[O:17]
Reactant: Cc1ccc(C[C@@H]2CN(Cc3cn[nH]c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C[C@@H]2CN(Cc3cnn(CCO)c3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C

Procedure:
Potassium carbonate (158 mg) and 2-bromoethanol (0.045 ml) were added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-pyrazolylmethyl)piperazine (300 mg) in N,N-dimethylformamide (3 ml) at room temperature with stirring. After stirring at 100° C. for 5 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by column chromatography (30 ml) on silica gel using a mixture of ethyl acetate and hexane (3:7) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methyl]piperazine (255.2 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([O:20]C)=O.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2sc3ccccc3c2S1(=O)=O
Yield: 60 %

Procedure:
Prepared analogous to Example 1 from methyl 4-hydroxy-2-methyl-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and aniline with a yield of 60% of theory.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([NH:19][CH2:20][C:21]2[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH2:43])=[O:42])[CH2:37][CH2:36]3)=[C:23]3[CH:31]=[N:30][N:29]([CH2:32][CH3:33])[C:24]3=[N:25][C:26]=2[CH2:27][CH3:28])=[O:18])=[CH:13][CH:12]=1.C(N(CC)C(C)C)(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[CH2:32]([N:29]1[C:24]2=[N:25][C:26]([CH2:27][CH3:28])=[C:21]([CH2:20][NH:19][C:17]([C:14]3[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)=[CH:12][CH:13]=3)=[O:18])[C:22]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH2:43])=[O:42])[CH2:37][CH2:36]3)=[C:23]2[CH:31]=[N:30]1)[CH3:33]
Reactant: C1COCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CNC(=O)c1ccc(CCCCOCCCCBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc2c(cnn2CC)c(NC2CCN(C(N)=O)CC2)c1CNC(=O)c1ccc(CCCCOCCCCN2CCOCC2)cc1
Temperature: 65 °C
Yield: 27.1 %

Procedure:
A mixture of 4-{[5-({[(4-{4-[(4-bromobutyl)oxy]butyl}phenyl)carbonyl]amino}methyl)-1,6-diethyl-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}-1-piperidinecarboxamide (1.1 g, 1.67 mmol, e.g. which can be as prepared in Intermediate 28) in N,N-dimethylformamide (20 ml) was treated with N,N-diisopropylethylamine (0.567 ml) and morpholine (0.300 ml, 3.3 mmol) and heated at 65° C. The solvent was removed under vacuum and the residue was applied directly to a 100 g silica SPE cartridge and eluted with a gradient of from 0% to 50% methanol in dichloromethane over 40 mins. Fractions containing product were pooled and evaporated to give a pale orange foam which appeared to be about 85% pure by analytical HPLC. The residue was further purified by mass directed preparative HPLC (Method C, using 0.1% trifluoroacetic acid) in 50 mg portions, and, following evaporation of the solvent from the appropriate fractions, the residual material was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution (NaHCO3). The organic fraction was collected by passing through a hydrophobic frit and evaporated to give the title compound (0.300 g) as a white foam. LCMS showed MH+=663; TRET=2.09 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH3:14]O>>[Cl:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(Cl)c(I)cc1C(=O)O
Reactant: CO
Product: COC(=O)c1cc(I)c(Cl)cc1OC
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 4-chloro-5-iodo-2-methoxybenzoic acid (2 g, 6.41 mmol) concentrated sulfuric acid (1.5 mL) in MeOH (50 mL) was stirred at reflux for 16 h. The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to afford the desired product (1.85 g, 85% yield) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH2:4][CH:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].F[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>>[CH3:12][N:2]([CH2:3][CH2:4][CH:5]([O:6][C:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][CH:21]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[CH3:1]
Reactant: Fc1cccc2ccccc12
Reactant: CN(C)CCC(O)c1cccs1
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
In this example, 2-acetylthiophene is used as the starting material for reacting with formaldehyde and dimethylamine to form a Mannich product namely 3-dimethylamino-1-(2-thienyl)propan-1-one. A hydride reduction is performed on this propanone to form corresponding 3-dimethylamino-1-(2-thienyl)propan-1-ol. The resulting propanol is then reacted with fluoronaphthalene to form N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. Subsequently, racemic Duloxetine® is obtained by demethylation of this propylamine. In this process, the yield of demethylation is very low, about 41%. In addition, Duloxetine® produced via this route is racemic. Resolution is therefore needed to obtain chiral Duloxetine which renders this process less competitive.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15].N#N.Cl>CCOC(C)=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]2[O:7][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:4]=2[CH2:5][CH2:6]1
Reactant: CC1(c2ccccc2)CCCC1=O
Reactant: O=C=NC(=O)Cl
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)CCc2c1oc(=O)[nH]c2=O
Temperature: 58 °C
Reaction time: 1.75 h
Yield: 43 %

Procedure:
Combined 2-methyl-2-phenylcyclopentanone (Intermediate V(1) (705.5 mg, 4.05 mmol) and carbonisocyanatidic chloride (1700 mg, 8.06 mmol), flushed with N2, and sealed in a sealed tube. Heated at 58° C. for 1 h, then 130° C. for 1.75 h. Let cool to rt. Carefully opened the tube (HCl), and dissolved the residue in EtOAc. Partitioned with NaHCO3 (aq), and extracted 3 times into EtOAc. Washed combined organic layers with brine, dried over MgSO4, filtered, and concentrated in vacuo. Loaded the residue onto Silica gel and eluted with an EtOAc/Hexane gradient to afford 7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (43% yield)LC-MS (M+H)+=244.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (1H, br. s.), 7.32-7.38 (2H, m), 7.26-7.30 (3H, m), 2.69-2.75 (2H, m), 2.43-2.52 (1H, m), 2.21-2.29 (1H, m), 1.68 (3H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@:16]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([CH2:25][C:26]4[CH:34]=[CH:33][CH:32]=[C:28]([C:29]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[O:30])[CH:27]=4)[C:17]3=[O:35])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1
Reactant: C1COCCN1
Product: O=C(c1cccc(CN2C(=O)[C@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1)N1CCOCC1

Procedure:
The title compound was prepared in analogy to Example 60 starting from morpholine, (3-bromomethyl)-benzoate (commercially available) and (1R,2S) and (1S,2R)-3-((2-(4-chlorophenyl)-2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)methyl)benzoic acid prepared as in Scheme 1. LC/MS m/e calcd. for C28H25ClN2O3: 472, observed (M+H)+: 473.2 1H NMR (400 MHz, MeOD-d4) δppm 2.15-2.27 (m, 2 H) 3.18-3.36 (m, 1 H) 3.47 (br. s., 4 H) 3.70 (br. s., 4 H) 5.11 (s, 2 H) 6.08 (d, J=7.58 Hz, 1 H) 6.71 (t, J=7.58 Hz, 1 H) 6.88 (d, J=8.08 Hz, 1 H) 7.01-7.12 (m, 1 H) 7.17-7.26 (m, 2 H) 7.25-7.40 (m, 4 H) 7.43-7.56 (m, 2 H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:32]1([C:38](=[O:44])[CH2:39][C:40](=O)[CH2:41][CH3:42])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:41](/[C:40](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:39]/[C:38](=[O:44])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:42]
Reactant: CCC(=O)CC(=O)c1ccccc1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CC/C(=C/C(=O)c1ccccc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.177 mmol) of Intermediate 51 and 34 mg (0.194 mmol) of Intermediate 16 to yield 30 mg of Example 17: TLC (DCM/MeOH (4:1): Rf=0.63; 1H NMR (DMSO-d6, 400 MHz) δ11.49 (d, 1H, J=9.6), 7.77 (m, 4H), 7.37 (m, 3H), 7.10 (d, 2H, J=8.8), 6.97 (d, 2H, J=9.2), 6.79 (d, 2H, J=9.2), 5.54 (s, 1H), 4.66 (septuplet, 1H, J=6.0), 4.12 (t, 2H, J=6.8), 4.04 (m, 1H), 3.35 (m, 1H), 3.11 (m, 1H), 2.84 (t, 2H, J=6.8), 2.72 (dd, 1H, J=13.9, 9.2), 2.28 (s, 3H), 1.99 (m, 2H), 1.26 (d, 6H, J=6.0), 0.91 (m 3H, J=7.6); low resolution MS (ES+)m/e 583.1 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:16]4[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([Cl:13])[CH:15]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: COc1ccc(N2CCNCC2)cc1Cl
Reactant: ClCc1cn2cc(Cl)ccc2n1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: COc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1Cl
Reaction time: 0.75 h
Yield: 62 %

Procedure:
A mixture of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.290 g), 1-(3-chloro-4-methoxyphenyl)piperazine (0.271 g), triethylamine (Aldrich; 0.159 g), and ethylene glycol (2 mL) is stirred at 80° C. for 40 min, at which time another 0.031 g of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine is added; after another 45 min, an additional 0.025 g of 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine is added. When the mixture has stirred for a total of 2 h, it is cooled and partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) to give 0.29 g of the title compound after crystallization from ethyl acetate/hexane; mp 99-100.5 ° C.; MS m/z 390, 392; IR (mineral oil) 1510, 1501, 795, 1072, 1321 cm-1. 1H NMR (CDCl3) δ2.75, 3.14, 3.78, 3.84, 6.83, 6.97, 7.13, 7.52, 7.55, 8.14.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:16])=[C:4]([S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C[O-].[Na+].Cl[CH2:21][S:22][C:23]#[N:24]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([S:16][CH2:21][S:22][C:23]#[N:24])=[C:4]([S:10]([N:13]([CH3:14])[CH3:15])(=[O:11])=[O:12])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: CN(C)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1S
Reactant: N#CSCCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)c1cc(Cl)c(Cl)c(Cl)c1SCSC#N
Temperature: 62 °C
Reaction time: 0.25 h

Procedure:
To a stirring mixture of 1.5 grams (0.0047 mole) of 3,4,5-trichloro-N,N-dimethyl-2-(mercapto)benzenesulfonamide in 80 milliliters of methanol at 25° C., was added 0.39 grams of sodium methoxide. The mixture was stirred for 15 minutes and thereafter 1.0 gram (0.009 mole) of chloromethylthiocyanate was added thereto and the mixture stirred at room temperature for 3 hours. At the end of this time period, the reaction mixture was filtered to remove the solids which had precipitated. The filtrate further heated at 62° C. for 2 hours and after cooling, the solvent was reduced in volume by evaporation under reduced pressure. The solids were thereafter removed by filtration. Additional filtrations gave additional solids. The recovered solids were combined and dissolved in chloroform and filtered. The solvent was removed by evaporation under reduced pressure and the solid product which remained was air dried. The 3,4,5-trichloro-N,N-dimethyl-2-(thiocyanomethyl)thio)benzenesulfonamide product was recovered in a yield of 0.7 grams (40 percent of theoretical) and melted at 155°-156° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34]O)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.[Br:41]Br>C(#N)C.C(OCC)C.CC#N.CCOCC>[Si:20]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][Br:41])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: BrBr
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1CO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1CBr

Procedure:
To a solution of triphenylphosphine (39.5 g, 0.15 mol), (2-((tert-butyldimethylsilyl)-oxy)phenyl)methanol (Ia) (12.23 g, 0.05 mol) and imidazole (10.5 g, 0.15 mol) in acetonitrile and diethyl ether (500 ml, CH3CN/Et2O=1:3, v/v) was added bromine (7.7 mL, 0.15 mol) dropwise at 0° C. with stirring. The reaction mixture was stirred at 0° C. for 20 minutes, during which time a white solid precipitated. The solution was carefully decanted and washed with brine (100 mL). The remaining solid was washed with diethyl ether (2×160 mL). All of the organic solutions were combined and concentrated. Hexane (200 ml) was added to the residue, and the solid was removed by filtration. The hexane solution was concentrated to provide the crude product. The product was purified by vacuum distillation (66-68° C. 0.093 Torr) reduced distillation to provide compound IIa (10.4 g, 67%) as a colorless oil.
Reaction SMILES: [C:1]([OH:8])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].CCN=C=N[CH2:14][CH2:15][CH2:16][N:17](C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1(N)CC1>>[CH:16]1([NH:17][C:1](=[O:8])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6])[CH2:14][CH2:15]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC/C=C/C(=O)O
Agent: NC1CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCC/C=C/C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.3 %

Procedure:
A flask equipped with an overhead stirred, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with (E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt (112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. The addition funnel was charged with NMM (99.1 mL, 1.6 mol) which was then added to the reaction mixture maintaining the temperature at 0±5° C. The mixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866 mmol) was added and the reaction allowed to warm to 25±5° C. over 16 hours. The reaction mixture was washed by adding hydrochloric acid (500 mL, 1.0 N) and the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the washing procedure repeated. Sodium hydroxide (500 mL, 1.0 N) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and base wash procedure repeated. Water (500 mL) was added and then the mixture stirred vigorously for 30 minutes then allowed to sit for 30 minutes; the layers were separated and the wash procedure repeated. The combined organic phases were concentrated under reduced pressure to ⅓ original volume then IPAc (600 mL) was added; this was repeated two times when a white precipate formed. The slurry was then concentrated under atmospheric pressure to ⅔ original volume then cooled to 50±5° C. N-heptane (890 mL) was slowly added while the reaction was cooled to −5±5° C. and held at this temperature for 4 hours. The solid was filtered, washed with cold n-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%) as a fine white solid.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[CH:11][C:10]=1[C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26]([CH3:34])([CH3:33])[O:27][SiH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:20].Cl[C:36](Cl)([O:38]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[C:29]([SiH2:28][O:27][C:26]([CH3:34])([CH3:33])[CH:22]1[CH2:23][CH2:24][CH2:25][N:21]1[C:19]([C:10]1[CH:11]=[C:12]([O:17][CH3:18])[C:13]([O:15][CH3:16])=[CH:14][C:9]=1[N:8]=[C:36]=[O:38])=[O:20])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1cc(N)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc(N=C=O)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reaction time: 2 h

Procedure:
A solution of triethylamine (1.35 eq.) in anhydrous toluene was added to the amine (5)(1 eq.) and triphosgene (0.36 eq.) in anhydrous toluene under a N2 atmosphere. The reaction was finished after 2 hours. (monitored by IR, ξNCO 2265 cm1). The product was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][C:18]([NH2:22])=[C:17]([NH2:23])[CH:16]=1.C(N(CC)CC)C>ClCCl>[NH2:23][C:17]1[CH:16]=[C:15]([Cl:14])[C:20]([Cl:21])=[CH:19][C:18]=1[NH:22][C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([C:12]#[N:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: COc1cc(C#N)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A solution of 2-methoxy-4-cyanobenzoyl chloride (2 g, 10 mmol) in dichloromethane (20 ml) was added dropwise in 1 h to a solution of 4,5-dichlorophenylendiamine (3.54 g, 20 mmol) and triethylamine (10.1 g=13.9 ml, 100 mmol) in dichloromethane (20 ml). Stirring was continued for additional two hours. The solvent was removed under vacuum and the residue was triturated with water (50 ml), filtered and dried at 50° C. under vacuum. The solid was suspended in diethyl ether (150 ml), stirred for 1 h, filtered and dried under vacuum to give 2.9 g of N-(2-amino-4,5-dichlorophenyl)-2-methoxy-4-cyanobenzamide (yield 43%), mp>250° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=1[Cl:39])[C:12]([C:14]1[S:28][C:17]2[C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][C:30]=1[Cl:39])[C:12]([C:14]1[S:28][C:17]2[C:18]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:19]=3[O:20][CH2:21][CH2:22][C:16]=2[CH:15]=1)=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2cc3c(s2)-c2c(C)cccc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1-c1sc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)c3ccc(C(=O)O)cc3Cl)cc1CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of methyl 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-10-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.250 g, 0.436 mmol) in tetrahydrofuran (10.2 mL, 126 mmol) and water (10.2 mL, 566 mmol) was added lithium hydroxide, monohydrate (0.0732 g, 1.74 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, acidified with 1M HCl, and extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-10-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (yield 60%). MS: (ESI+) 559.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:21])([F:20])[C:15]([O:17]CC)=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[Li].[CH2:24](OCC)C.[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([F:20])([F:21])[C:15]([CH3:24])=[O:17])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)C(F)(F)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h

Procedure:
Ethyl (4′-bromobiphenyl-4-yl)(difluoro)acetate (1.8 g, 5.1 mmol) obtained in Example 30-(1) was dissolved in tetrahydrofuran (20 mL), and a solution of methyllithium in diethyl ether (1.1 M, 14 mL, 15 mmol) was added under a nitrogen atmosphere at −78° C., followed by stirring at the same temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the extract was concentrated under reduced pressure to afford 1-(4′-bromobiphenyl-4-yl)-1,1-difluoroacetone as a pale yellow oil.