Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:36])[CH:3]([N:17]1[CH:20](S(O)=O)[CH:19]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:35])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5].[I:37]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][C:2](=[CH2:36])[CH:3]([N:17]1[CH:20]([I:37])[CH:19]([NH:24][C:25](=[O:34])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:18]1=[O:35])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C1CCC(=O)N1I
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)O
Solvent: ClCCl
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1I

Procedure:
A solution of p-nitrobenzyl 3-methyl-2-(2-oxo-4-sulfino-3-phenoxyacetamido-1-azetidinyl)-3-butenoate in methylene chloride was cooled to 0° C. and one molar equivalent of N-iodosuccinimide was added with stirring. After 5 minutes the reaction mixture was washed with brine, dried and evaporated. The product obtained as a solid residue was shown by its nmr spectrum to contain about a 2:1 ratio of cis-isomer to trans-isomer contaminated with a trace of oxazolineazetidinone.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]([NH:13][NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:37])[C@@H:10]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([Cl:35])[C:28]=1[CH3:36])[C:11]1[O:25][C:15]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc([N+](=O)[O-])cc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(N[C@@H](c2nnc(-c3ccc([N+](=O)[O-])cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 66.9 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoyl)-4-nitrobenzohydrazide (8.5 g, 15.57 mmol) in CH2Cl2 (250 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (8.17 g, 31.13 mmol), iodine (7.90 g, 31.13 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 50 minutes and quenched with sat. aq. sodium thiosulfate (400 mL). The solution was extracted with CH2Cl2 (250 mL). The organic extract was washed with sat. aq. sodium thiosulfate (300 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20-40% EtOAc in hexanes) to provide the title compound as a light yellow solid (5.5 g, 67%): 1H NMR (400 MHz, CDCl3, δ in ppm) 8.37 (dm, J=9.0 Hz, 2H), 8.18 (dm, J=9.0 Hz, 2H), 7.36 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H), 5.11 (d, J=9.2 Hz, 1H), 4.87 (dd, J=3.9, 8.8 Hz, 1H), 4.46 (dq, J=3.7, 6.3 Hz, 1H), 2.34 (s, 3H), 1.31 (d, J=6.3 Hz, 3H), 0.93 (s, 9H), 0.15 (s, 3H), 0.12 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1.[SH:15][C:16]1[NH:17][C:18]2[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:19]=2[N:20]=1>C(O)C.[OH-].[Na+]>[CH3:26][O:25][C:23]1[CH:22]=[CH:21][C:19]2[NH:20][C:16]([S:15][CH2:2][C:3]3[N:8]=[C:7]([N:9]4[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]4)[CH:6]=[CH:5][N:4]=3)=[N:17][C:18]=2[CH:24]=1
Reactant: ClCc1nccc(N2CCCCC2)n1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2[nH]c(SCc3nccc(N4CCCCC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.1 %

Procedure:
A mixture of 2-chloromethyl-4-piperidinopyrimidine (2.89 g) and 2-mercapto-5-methoxybenzimidazole (2.46 g) in ethanol (40 ml) and lN sodium hydroxide (15 ml) was stirred at room temperature for 16 hours. After stripping the residue was washed with water and recrystallised from acetonitrile to give 5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (3.5 g) m.p. 145°-147°.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[NH:13]2)=[O:11])=[CH:5][CH:4]=1.[C:32](Cl)(Cl)=[O:33].N1C=CC=CC=1>C(Cl)Cl.C1(C)C=CC=CC=1>[O:11]=[C:10]1[N:12]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:13]2[C:32](=[O:33])[N:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:30])[F:31])=[CH:4][CH:5]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)N1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1n(-c2ccc(C(F)(F)F)cc2)c(=O)n2n1CC(c1ccccc1)C2c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To 2.0 g (4.4 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-phenyl-2,3,4,5-tetrahydro-1H-pyrazole-1-carboxamide (Example 3) in 5 ml of methylene chloride was added 4.2 ml (8 mmole) of 1.9M phosgene in toluene. After stirring for 5 minutes 0.8 g (10 mmole) of pyridine was added. The mixture was stirred for 1 hour and then partitioned between diethyl ether and dilute aqueous hydrochloric acid. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. Filtration, concentration in vacuo, and chromatography on silica gel using diethyl ether and hexanes gave the title compound, mp 148°-150° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7].[CH3:31][O:32][CH2:33]Cl>C1COCC1>[CH3:3][O:4][N:5]([CH3:30])[C:6]([C:8]1[C:13]([N:14]([CH2:31][O:32][CH3:33])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)(=[O:17])=[O:16])=[CH:12][C:11]([Cl:29])=[CH:10][N:9]=1)=[O:7]
Reactant: CON(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a mixture of sodium hydride (164 mg, 4.10 mmol) in 5 mL of THF was added a mixture of 5-chloro-3-(4-methyl-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid methoxy-methyl-amide (1.50 g, 3.42 mmol) and chloromethyl methyl ether (0.388 mL, 5.13 mmol) in 5 mL of THF. The mixture was stirred at room temperature overnight. After the removal of the solvents the residue was purified by flash column (20% ethyl acetate in hexane) to afford 1.50 grams of the title compound as a white solid: (M++H) expect 482.0, found 482.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[NH2:11][C:12](=[S:19])[CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[CH3:20]CO>>[C:5]1([C:3]2[N:11]=[C:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:20])=[O:16])[S:19][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)CCC(N)=S
Reactant: CCO
Product: CCOC(=O)CCc1nc(-c2ccccc2)cs1
Temperature: 80 °C
Yield: 40 %

Procedure:
A mixture of 2-bromo acetophenone (2.1 g, 10.55 mmol) and methyl 4-amino-4-thioxobutanoate (1.6 g, 10.86 mmol) in EtOH (15 mL) was heated to 80° C. for 3 h. Reaction mixture was cooled to room temperature and solvent was evaporated under reduced pressure. The product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford ethyl 3-(4-phenylthiazol-2-yl)propanoate (1.1 g, yield 40%) as a white solid, which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.90-7.87 (m, 2H), 7.44-7.39 (m, 2H), 7.35-7.30 (m, 2H), 4.22-4.15 (q, J=7.2 Hz, 2H), 3.41-3.36 (t, J=7.5 Hz, 2H), 2.94-2.89 (t, J=7.3 Hz, 2H), 1.30-1.25 (t, J=7.1 Hz, 3H). MS (ESI) m/z: Calculated for C14H15NO2S: 261.08. found: 262.2 (M+H)+.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)C.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:51])[C:43]2[C:48]([CH:49]=O)=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:42]([CH3:51])[C:43]2[C:48]([CH:49]=[C:2]([CH3:3])[CH3:1])=[CH:47][CH:46]=[CH:45][N:44]=2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [Li]CCCC
Reactant: CN(c1ncccc1C=O)C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)=Cc1cccnc1N(C)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M, 8.1 ml, 12.93 mmol) is added to a suspension of isopropyltriphenylphosphonium iodide (5.6 g, 12.93 mmol) in dry THF. The ylide is allowed to generate for 45 min at 20°-25° under nitrogen before a solution of 1-benzyl-4-[N-methyl-N-(3-(formyl)-2-pyridinyl)amino]piperidine (XXI, EXAMPLE 13, 2.0 g, 6.5 mmol) in dry THF is added. The reaction is stirred an additional 30 min before being quenched with water and extracted with chloroform. The extracts are washed with saline and dried (sodium sulfate). Removal of the solvent gives a residue which is chromatographed (silica gel, 4×35 cm column; ethyl acetate/hexane (1/3→1/1) to give the title compound, NMR (300 MHz, CDCl3) 1.55-1.65, 1.74, 1.79-1.85, 1.85, 2.75, 2.87-2.90, 3.40-3.48, 3.42, 5.97, 6.69, 7.16-7.28 and 8.04δ.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[C:29]5[C:24](=[CH:25][C:26]([N+:30]([O-])=O)=[CH:27][CH:28]=5)[C:23]([CH2:33][C:34]([O:36][CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[O:35])=[CH:22]4)=[O:20])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:19]([C:16]1[CH:17]=[CH:18][C:12]3[O:11][C:10]([C:7]4[S:8][CH:9]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[N:6]=4)=[CH:14][C:13]=3[CH:15]=1)=[O:20])[CH:22]=[C:23]2[CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35]
Reactant: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(CC(=O)OCc5ccccc5)c5cc([N+](=O)[O-])ccc54)ccc3o2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1csc(-c2cc3cc(C(=O)n4cc(CC(=O)OCc5ccccc5)c5cc(N)ccc54)ccc3o2)n1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A mixture of benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}-5-nitroindol-3-acetate (450 mg), iron powders (450 mg) and ammonium chloride (45 mg) in a mixed solvent of ethanol (7 ml) and water (3 ml) was stirred under reflux for 1 hour. After being cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give benzyl 5-amino-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]carbonyl}indole-3-acetate (259 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][CH:24]=2)[C:5]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)=[C:6]([C:8](N(OC)C)=[O:9])[CH:7]=1.Cl[Mg][CH2:28][CH3:29]>>[Cl:1][C:2]1[C:3]2[N:4]([C:22]([CH3:25])=[N:23][CH:24]=2)[C:5]([C:14]2[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=2)=[C:6]([C:8](=[O:9])[CH2:28][CH3:29])[CH:7]=1
Reactant: CON(C)C(=O)c1cc(Cl)c2cnc(C)n2c1-c1cc(F)cc(F)c1
Reactant: CC[Mg]Cl
Product: CCC(=O)c1cc(Cl)c2cnc(C)n2c1-c1cc(F)cc(F)c1
Yield: 39 %

Procedure:
The desired compound was prepared by the procedure of Example 1, step J using 8-chloro-5-(3,5-difluorophenyl)-N-methoxy-N,3-dimethylimidazo[1,5-a]pyridine-6-carboxamide and chloro(ethyl)magnesium as the starting materials in 39% yield. LCMS calculated for C17H14ClF2N2O (M+H)+: m/z=335.1. found: 334.9.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])=[C:7]([C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])=[O:10])[O:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24](=[O:26])[CH3:25]>>[CH3:22][O:23][C:24](=[O:26])[CH2:25][C:2]1[CH:21]=[CH:20][CH:5]=[C:4]([C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])=[C:7]([C:9](=[O:10])[C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=4[Cl:18])[O:8][C:4]=3[CH:3]=2)[CH:3]=1
Reactant: COC(C)=O
Reactant: Cc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc(Br)ccc12
Product: COC(=O)Cc1cccc(-c2ccc3c(C)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1

Procedure:
{3-[2-(2,4-Dichloro-benzoyl)-3-methyl-benzofuran-6-yl]-phenyl}-acetic acid methyl ester was prepared via a Suzuki coupling of (6-Bromo-3-methyl-benzofuran-2-yl)-(2,4-dichloro-phenyl)-methanone and 3-Bromo-phenyl)-acetic acid methyl ester as described in method 1 step 5. MS ES (MH+)453.1, RT=4.27 min).
Reaction SMILES: C1(C)C=CC=CC=1.[Si:8]([O:15][CH2:16][C@@H:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CO[CH:25](O)[C:26]([F:29])([F:28])[F:27]>O>[Si:8]([O:15][CH2:16][C@@H:17](/[N:22]=[CH:25]/[C:26]([F:29])([F:28])[F:27])[CH2:18][CH:19]([CH3:20])[CH3:21])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: COC(O)C(F)(F)F
Reactant: CC(C)C[C@H](N)CO[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)/N=C/C(F)(F)F

Procedure:
A toluene (300 mL) solution of (2S)-1-{[tert-butyl(dimethyl)silyl]oxy}-4-methylpentan-2-amine from Step 1 (50 g) and trifluoroacetaldehyde methyl hemiacetal (35 mL) was heated to reflux for 16 hours during which time water was collected in a Dean-Stark trap. The solvent was evaporated in vacuum and the residue was purified on SiO2 using hexanes and ethyl acetate (9:1) as eluant to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.[O:25]=[S:26]1(=[O:40])[CH2:31][CH2:30][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:40]=[S:26]1(=[O:25])[CH2:27][CH2:28][N:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:22]([C:19]3[CH:18]=[CH:17][C:16]([C:3]4[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9]([C:11]5[S:12][CH:13]=[CH:14][CH:15]=5)=[O:10])[CH:4]=4)=[CH:21][CH:20]=3)=[O:23])=[CH:35][CH:34]=2)[CH2:30][CH2:31]1
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1

Procedure:
2′-Methyl-5′-[(thiophene-2-carbonyl)-amino]-biphenyl-4-carboxylic acid (45 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (32 mg), EDAC (25 mg), HOBT (18 mg) and N-methylmorpholine (27 mg) in dry DMF (0.5 ml) was stirred at 20 C for 18 h. The mixture was then diluted with water (6 ml) and the resulting colourless solid collected by filtration and dried (62 mg).
Reaction SMILES: [SH2:1].[C:2]([O:6][CH3:7])(=[O:5])[CH:3]=[CH2:4]>[OH-].[NH4+]>[SH:1][CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5].[S:1]([CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5])[CH2:4][CH2:3][C:2]([O:6][CH3:7])=[O:5]
Reactant: S
Reactant: C=CC(=O)OC
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)CCS
Product: COC(=O)CCSCCC(=O)OC

Procedure:
reacting hydrogen sulfide with methyl acrylate in the presence of an ammonium hydroxide catalyst to give a mixture comprising methyl 3-mercaptopropionate and dimethyl thiodipropionate; and
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:21](=[O:22])[CH:20]3[C:15](=[CH:16][CH2:17][CH2:18][CH2:19]3)[C:14]2=[O:23])=[CH:8][C:7]=1[S:24][C:25]1([C:28](O)=[O:29])[CH2:27][CH2:26]1>CN(C)C=O.C(Cl)CCl>[Cl:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:21](=[O:22])[CH:20]3[C:15](=[CH:16][CH2:17][CH2:18][CH2:19]3)[C:14]2=[O:23])=[CH:8][C:7]=1[S:24][C:25]1([C:28]([Cl:3])=[O:29])[CH2:27][CH2:26]1
Reactant: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)O)CC2)c(Cl)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C1C2=CCCCC2C(=O)N1c1cc(SC2(C(=O)Cl)CC2)c(Cl)cc1F
Temperature: 25 °C

Procedure:
While stirring at room temperature, 3 ml of thionyl chloride are added to a solution of 1 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid and one drop of dimethylformamide in 40 ml of ethylene chloride and the reaction mixture is then heated under reflux for 3 hours. Concentration of the reaction mixture by evaporation yields 1 g of 1-[2-chloro-4-fluoro-5-(1,2,3,4,5,6-hexahydro-1,3-dioxo-isoindolyl)-phenylthio]-cyclopropanecarboxylic acid chloride in the form of an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:21][S:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:33][CH:32]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(=O)NCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-methylsulphonylbenzoic acid.
Reaction SMILES: [C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OCC)=O)=N\C(OCC)=O>C1COCC1>[C:1]1([CH:7]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([O:10][C@H:20]2[CH:21]3[CH2:24][CH2:25][N:18]([CH2:23][CH2:22]3)[CH2:19]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(Nc1ccccc1)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.5 %

Procedure:
To a solution of 2-phenyl-2-(phenylamino)acetic acid (I1) (500 mg, 2.20 mmol), (R)-quinuclidin-3-ol (280 mg, 2.20 mmol) and triphenylphosphine (577 mg, 2.20 mmol) in dry THF (7 mL) cooled at 0° C., is added (E)-diethyl diazene-1,2-dicarboxylate (0.35 mL, 2.20 mmol) and the reaction is stirred for 2 hours at RT. The solvent is removed under vacuum and the residue is taken up with EtOAc, washed with 5% NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness. The resulting yellow oil is purified by flash chromatography (EtOAc/MeOH/NH4OH=90/10/0.1 to 70/30/0.1) to obtain desired product as a white powder (78.0 mg, 10% yield, mixture of diasteroisomer).
Reaction SMILES: Cl.[CH3:2][C@H:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1.[Br:9][C:10]1[N:15]=[C:14]([C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=1>>[Br:9][C:10]1[N:15]=[C:14]([C:16]([N:5]2[CH2:6][CH2:7][O:8][C@H:3]([CH3:2])[CH2:4]2)=[O:17])[CH:13]=[CH:12][CH:11]=1
Reactant: C[C@@H]1CNCCO1
Reactant: O=C(O)c1cccc(Br)n1
Agent: Cl
Product: C[C@@H]1CN(C(=O)c2cccc(Br)n2)CCO1

Procedure:
The title compound was prepared as described in Example 283, Step 1 using (2R)-2-methylmorpholine hydrochloride (124 mg, 0.90 mmol) and 6-bromopyridine-2-carboxylic acid (150 mg, 0.74 mmol) as starting materials.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])[C:4]=2[N:5]=[C:6]([S:8][CH3:9])[N:7]=1.[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[N:10]1[C:4]2[N:5]=[C:6]([S:8][CH3:9])[N:7]=[C:2]([C:25]3[CH:26]=[C:27]([CH:31]=[CH:32][C:24]=3[CH3:23])[C:28]([OH:30])=[O:29])[C:3]=2[CH:13]=[CH:12][C:11]1=[O:14]
Reactant: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CSc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
The solution of 4-chloro-8-(2,6-difluorophenyl)-2-(methylthio) pyrido[2,3-d]pyrimidin-7(8H)-one (1.70 g, 5.00 mmol) in DME (150 mL) and H2O (50 mL), in a pressure flask (500 mL, Chemglass), was added 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)benzoic acid (1.97 g, 7.50 mmol) and K2CO3 (4.15 g, 30.0 mmol). The resulting mixture was degassed with Argon for 5 minutes, mixed with Pd(PPh3)4 (0.232 g, 0.20 mmol) and heated with a preheated oil bath (160° C.) under vigorous stirring for 30 minutes. The reaction mixture was filtered through celite, concentrated under vacuum to remove DME. It was then mixed with EtOAc (200 mL) and AcOH (2.5 mL), and shaked. The layers were separated. The organic layer was collected, further washed with brine (70 mL), dried over Na2SO4, filtered, concentrated and purified via a flash chromatography (load column with DCM, mobile phase EtOAc/Hexane) to afford the title compound as a white solid 2.15 g (98%). LC-MS (ES) m/z 440 (M+H)+; 1H-NMR (MeOD) δ 2.27 (s, 3 H), 2.31 (s, 3 H), 6.71 (d, J=9.6 Hz, 1 H), 7.28 (t, J=8.2 Hz, 2 H), 7.57 (d, J=8.4 Hz, 1 H), 7.64 (m, 2 H), 8.00 (d, J=1.6 Hz, 1 H), 8.14 (dd, J=7.6 Hz, J2=1.6 Hz, 1 H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[C:26]4[C:22]([C:23](C)=[N:24][N:25]4C)=[CH:21][CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1[N:42]=NN2C=CC(B(O)O)=CC=12>>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:27]=[CH:26][N:25]4[N:24]=[N:42][C:22]([CH3:23])=[C:21]4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(C)nn(C)c4c3)sc2c1-c1ccc(Cl)cc1
Reactant: Cc1nnn2ccc(B(O)O)cc12
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccn4nnc(C)c4c3)sc2c1-c1ccc(Cl)cc1

Procedure:
Prepared in a manner similar to (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(1,3-dimethyl-1H-indazol-6-yl)-5-methylbenzo[d]thiazol-6-yl)acetate, but using 3-methyl-[1,2,3]triazolo[1,5-a]pyridin-5-ylboronic acid instead of 1,3-dimethyl-1H-indazol-6-ylboronic acid. 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J=7.4 Hz, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.66 (dd, J=7.4, 1.6 Hz, 1H), 7.61-7.50 (m, 3H), 7.50-7.43 (m, 1H), 5.17 (s, 1H), 4.27-4.17 (m, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.30-1.22 (m, 3H), 0.99 (s, 9H).