Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6].O=S(Cl)Cl.[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH2:11][CH3:12])[CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: CCc1cc(Br)cc(C(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCc1cc(Br)cc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 10 h
Yield: 92 %

Procedure:
The compound 3-bromo-5-ethylbenzoic acid (0.95 g, 4.14 mmol) was dissolved in MeOH (50 mL), reaction mixture was cooled to 0° C. and SOCl2 (0.5 mL) was added. The reaction mixture was allowed to stir at room temperature for 10 h. The reaction mixture was concentrated under reduced pressure and diluted with CH2Cl2. The organic layer was washed with 10% NaHCO3 solution, water and brine. The organic phase was dried over anhydrous sodium sulfate and solvent was removed under reduced pressure. Methyl 3-bromo-5-ethylbenzoate (0.92 g, yield 92%) was isolated as colorless liquid and carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.99 (t, J=1.6 Hz, 1H), 7.81 (d, J=1.4 Hz, 1H), 7.54 (t, J=1.6 Hz, 1H), 3.92 (s, 3H), 2.69 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([OH:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12](N(CC)CC)[CH3:13].ICC>CN(C=O)C>[CH2:12]([S:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)(=[O:11])=[O:10])[CH3:13]
Reactant: CCN(CC)CC
Reactant: O=S(O)c1ccc(F)c(F)c1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(F)c(F)c1
Temperature: 90 °C

Procedure:
To 3.0 mmol 3,4-difluoro-benzenesulfinic acid and 3.0 mmol triethylamine in 10 ml DMF was added 7.5 mmol iodoethane and the mixture heated at 90° C. for 9 h. The reaction mixture was then poured onto water and extracted three times with ethyl acetate. The combined organic phases were then washed twice with saturated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel (eluant: ethyl acetate/heptane 1:7) to afford the title compound. MS (m/e): 206.9 (M+H+, 100%)
Reaction SMILES: B1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C2CCCC1CCC2.Br[C:18]1[C:23]2[O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]3[C:22]=2[CH:21]=[C:20]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:10]([C:18]1[C:23]2[O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH:26]3[C:22]=2[CH:21]=[C:20]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3c(Br)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2Oc3c(Cc4ccccc4)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
B-Benzyl-9-BBN (1.3 mL 0.5 M sol in THF, 0.650 mmol) was added to degassed DMF (3 mL), followed by sequential addition of tert-butyl 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.255 g, 0.511 mmol), catalyst Cl2PdDPPF (0.018 g, 0.022 mmol) and K2CO3 (0.220 g, 1.592 mmol). The reaction mixture was stirred under N2 at 65° C. for 6 h. The reaction mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography (14% EtOAc/Hexane) and tert-butyl 6-benzyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in 77% yield (0.200 g, 0.392 mmol). MS (ESI+) for C29H29Cl2NO3 m/z 510.1 (M+H)+.
Reaction SMILES: [CH:1]([N:3]([CH3:6])[CH2:4][OH:5])=O.[Cl:7][C:8]1[C:12]([Cl:13])=[C:11]([C:14]([NH2:16])=[O:15])[S:10][N:9]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[CH:4]([N:3]([CH2:1][NH:16][C:14]([C:11]1[S:10][N:9]=[C:8]([Cl:7])[C:12]=1[Cl:13])=[O:15])[CH3:6])=[O:5]
Reactant: NC(=O)c1snc(Cl)c1Cl
Reactant: CN(C=O)CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CN(C=O)CNC(=O)c1snc(Cl)c1Cl
Yield: 47.1 %

Procedure:
At room temperature, 15 g (0.164 mol) of N-formyl-N-hydroxymethyl-methylamine are added with stirring to a mixture of 32.3 g (0.164 mol) of 3,4-dichloro-isothiazole-5-carboxamide and 245 ml of glacial acetic acid. At room temperature, 37 g (0.362 mol) of concentrated sulphuric acid are then added dropwise with stirring, the reaction mixture being cooled with ice. The reaction mixture is subsequently stirred at room temperature for 29 hours and then, with ice-cooling, admixed with 400 ml of water. The resulting mixture is extracted four times with 200 ml of methylene chloride and the combined organic phases are dried over sodium sulphate and then concentrated under reduced pressure. The oily residue that remains is chromatographed over silica gel using ethyl acetate. Concentration of the eluate gives 20.7 g (42.6% of theory) of N-(N-formyl-N-methyl-aminomethyl)-3,4-dichloroisothiazole-5-carboxamide in the form of a crystalline solid of melting point 87 to 88° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:6][C:5]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[C:3]=1[C:20](=[S:23])[NH:21][CH3:22].O1CCCC1.[BH4-].[Na+]>CO>[OH:1][CH:2]1[C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[O:6][C:5]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:4]=2[CH:3]1[C:20](=[S:23])[NH:21][CH3:22]
Reactant: CNC(=S)C1=C(O)C2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC2(CCOCC2)C1O
Reaction time: 24 h
Yield: 45.7 %

Procedure:
To a mixture of 3.7 g of 3-hydroxy-N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide, 100 ml of tetrahydrofuran and 100 ml of methanol was added 2.8 g of sodium borohydride (NaBH4) with stirring under ice-cooling, and the mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 24 hours. The reaction solution was vacuum-distilled, water was added therein and the resultant mixture was extracted with methylene chloride. An organic layer was washed with water and dried. The solvent was distilled to obtain 1.7 g of 3,4-dihydro-3-hydroxy-N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide. Subsequently, to 1.5 g of it were added 2.1 g of p-toluenesulfonyl chloride and 60 ml of pyridine. After the mixture was refluxed with heating for 1 hour, the solvent was distilled. Ice water was added to the residue and the reaction solution was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The residue was purified according to silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 1.2 g of N-methyl-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carboxamide with a melting point of 183°-184° C.
Reaction SMILES: O(P(O[C:18]1[CH2:19][C@@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:42][C@@H:43]1[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])[C@H:45]([CH:61]2[N:64]([CH3:65])[C:63](=[O:66])[CH2:62]2)[CH2:44]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:42][C@@H:43]3[CH2:47][N:46]([C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[C@H:45]([CH:61]4[N:64]([CH3:65])[C:63](=[O:66])[CH2:62]4)[CH2:44]3)[CH2:19][C@H:20]12)[CH3:39]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)C[C@H]12
Reactant: CN1C(=O)CC1[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Yield: 95.2 %

Procedure:
The same procedure as in Example 1-1 was carried out by using p-nitrobenzyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (235 mg, 0.40 mmol) and (2S,4S)-4-mercapto-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidine (149 mg, 0.41 mol, compound of Reference Example 7) to obtain p-nitrobenzyl (5R,6S)-6-[(R)-1-hydroxyethyl]-2-[(2S,4S)-2-(N-methyl-2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate (265 mg, yield: 94.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: COc1cc(CO)cc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of [2-chloro-6-(methyloxy)-4-pyridinyl]methanol (for a synthesis see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry DMF (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at rt for 2 h. The reaction mixture was treated with water extracted three times with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluting with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%).
Reaction SMILES: O1CCCC1.[O:6]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[CH2:8][C:9]([O:11]CC)=[O:10].[OH-].[Li+:26]>O>[O:6]=[C:7]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=1)[CH2:8][C:9]([O-:11])=[O:10].[Li+:26]
Reactant: CCOC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])CC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a tetrahydrofuran (350 ml) solution of ethyl 3-oxo-3-{[3-(trifluoromethyl)phenyl]amino}propanoate (5 g, 18.17 mmol) (Example 1A) is added lithium hydroxide (435 mg, 18.17 mmol) in water (150 ml). The solution is stirred at room temperature for 4 hours, and then concentrated to afford a white solid. The crude product is used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>C(COC)OC>[CH2:35]([O:34][C:32]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(OCc1ccccc1)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.7 %

Procedure:
To a solution of 5.0 g (0.014 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole in 50 ml glyme was added 1.7 g (0.015 mole) of potassium t-butoxide. The mixture was cooled and a solution of 5.0 g (0.029 mole) of benzyl chloroformate in 25 ml glyme was added dropwise. The reaction mixture was stirred at room temperature overnight, then poured onto water. The mixture was extracted with ether and the combined ether extracts were washed, then dried and concentrated to give 12.1 g of crystals. The product was purified by chromatography on silica gel, eluting with toluene, to give 2.1 g of colorless crystals (from hexane), mp 110°-111°.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Cl.Br[C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][NH:39][CH2:38]2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:38]1[C:37]2[C:41](=[CH:42][C:43]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]3)=[CH:35][CH:36]=2)[CH2:40][NH:39]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: Brc1ccc2c(c1)CNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc5c(c4)CNC5)cc23)CC1
Yield: 7.5 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (150 mg, 0.325 mmol) in dioxane (0.75 mL) and water (0.25 mL), was added 5-bromo-2,3-dihydro-1H-isoindole hydrochloride (130 mg, 0.651 mmol), and cesium carbonate (636 mg, 1.952 mmol). The reaction mixture was kept under argon for 10 min before addition of tetrakis(tripehnylphosphine)palladium(0) (19 mg, 0.016 mmol). The resultant mixture was heated in a microwave for 20 min at 150° C. Mixture was then purified by HPLC to give 11 mg of the title compound.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][NH:27][C:23]3[N:22]=[N:21][CH:26]=[CH:25][N:24]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Nc1nccnn1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CNc2nccnn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1,2,4-triazin-3-amine. m/e+ 331 for C19H19N6 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.53 (d, J=9.1 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 7.05 (dd, J=1.4, 9.1 Hz, 1H), 5.11 (s, 2H), 2.37 (s, 3H), 2.27 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23](Br)=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]1(B(O)O)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>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>[C:34]1([C:23]2[C:18]3[N:19]([CH:25]=[C:16]([C@@H:12]4[CH2:13][CH2:14][CH2:15][N:11]4[C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[N:17]=3)[CH:20]=[CH:21][CH:22]=2)[C:35]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Reactant: OB(O)c1cccc2ccccc12
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+]
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(-c3cccc4ccccc34)c2n1
Yield: 66.1 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.250 g, 0.62 mmol), 1-napthyl boronic acid (0.1405 g, 0.82 mmol), potassium carbonate (0.1340 g, 0.97 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.0430 g, 0.04 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4 g SiO2, 0-50% ethyl acetate in hexanes) to give (2S)-benzyl 2-(8-(naphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.183 g, 0.41 mmol, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.[O:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Reactant: OC1CCOCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccc(Cl)cc2CCc2c(OC3CCOCC3)cccc21
Yield: 45 %

Procedure:
For the synthesis of the title compound, 0.45 g (1.7 mmol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.28 g (0.0027 mol) of tetrahydropyran-4-ol, 0.77 g (2.9 mmol) of P(Ph)3 and 0.41 g (2.0 mmol) of diisopropyl azodicarboxylate in 2 ml of THF are reacted by method P. C20H19ClO3 (Mr=342.83); yield: 45%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH2:10]1[C:13]2([CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]1[CH2:17][CH2:18][OH:19]>>[Br:1][C:2]1[N:3]=[C:4]([CH2:8][O:19][CH2:18][CH2:17][N:11]2[CH2:12][C:13]3([CH2:16][CH2:15][CH2:14]3)[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1cccc(Br)n1
Reactant: OCCN1CC2(CCC2)C1
Product: Brc1cccc(COCCN2CC3(CCC3)C2)n1

Procedure:
The title compound was prepared according to Example 251, Step 1 using 2-bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (200 mg, 0.80 mmol) and 2-(2-azaspiro[3.3]hept-2-yl)ethanol (112 mg, 0.80 mmol) as the starting materials.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:36]2[CH:35]=[C:34]([C:20]3[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[N:21]=3)[CH:39]=[CH:38][N:37]=2)[CH:41]=1)(=[O:47])=[O:48]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 57.6 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.114 g, 1.08 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.127 g, 57%). MS (ISP) 613.2 [(M+H)+]; mp 186° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8](C(C3C=CC=CC=3)=O)[CH:9]=[CH:10][C:5]2=[C:4]([Cl:19])[CH:3]=1.[OH-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:19])[CH:3]=1
Reactant: O=C(c1ccccc1)n1ccc2c(Cl)cc(Br)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1cc(Br)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(6-Bromo-4-chloro-pyrrolo[2,3-b]pyridin-1-yl)-phenyl-methanone (1 eq, 69.7 mmol, 23.4 g) is dissolved in MeOH (300 ml), then aqueous NaOH solution (1 M, 120 ml) is added and the resulting mixture is stirred for 18 h at r.t. The mixture is extracted with DCM and EtOAc, the extracts are combined and the solvents are removed in vacuo. Recrystallization from MeOH yields the title compound; [M+H]+=231.
Reaction SMILES: Cl.[S:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[NH:4][CH2:3]1.[N:11]([O-])=[O:12].[Na+]>CC(O)=O.O>[N:11]([N:4]1[CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7][S:2][CH2:3]1)=[O:12]
Reactant: O=C(O)C1CCSCN1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CSCCC1C(=O)O
Reaction time: 3 h

Procedure:
To a suspension of DL-tetrahydro-1,3-thiazine-4-carboxylic acid hydrochloride (48.6 g, 0.26 mol) in 666 mL of AcOH was added to the solution of 27.4 g (0.40 mol) of NaNO2 in 333 mL of water over 16 min at room temperature and stirred for 3 h. The solution was concentrated under reduced pressure. Acetone (300 mL) was added to the residue and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to dryness and crude 3-nitroso[1,3]thiazinane-4-carboxylic acid was obtained as brown amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:16])=[C:12]([CH3:15])[N+:13]=2[O-])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O.N>C(Cl)(Cl)Cl>[Cl:19][CH2:15][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][C:11]=1[CH3:16]
Reactant: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 0 °C

Procedure:
82 g of 2-(4-Methoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide are dissolved in 400 ml of chloroform, 37.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0° C., the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4, and the solvent then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=80:1=>5:1. This gives 46.3 g of 4-chloromethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole as a yellow solid. C12H12ClNO2 (237.69), MS (ESI)=238 (M+H+), Rf (n-heptane:ethyl acetate)=7:3)=0.45.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[N+:23]([C:26]1[CH:27]=[C:28]([CH2:32][S:33](Cl)(=[O:35])=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[C:28]([CH:29]=[CH:30][CH:31]=1)[CH2:32][S:33]([NH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1)(=[O:35])=[O:34])([O-:25])=[O:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(NS(=O)(=O)Cc2cccc([N+](=O)[O-])c2)c1
Yield: 99.2 %

Procedure:
Into a 1-neck round-bottom flask was added tert-butyl (3-aminophenyl)carbamate (1.0 g, 4.8 mmol) and tetrahydrofuran (20 mL) and triethylamine (1.0 mL, 7.2 mmol). The mixture was cooled in an ice bath and (3-nitrophenyl)methanesulfonyl chloride (1.1 g, 4.8 mmol) was slowly added. The resultant mixture was warmed to rt. The solvent was removed under vacuum and EtOAc and water added. The aqueous phase was extracted again with EtOAc. The organic layers were combined, dried over Na2SO4 and the solvent removed under vacuum to give the desired product (1.94 g, 99%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, DMSO-d6): δ 9.84 (s, 1H), 9.37 (s, 1H), 8.98 (s, 1H), 8.19 (ddd, J=8.1, 2.3, 1.1 Hz, 1H), 8.11 (t, J=1.9 Hz, 1H), 7.71 (dt, J=7.7, 1.3 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.44 (t, J=2.0 Hz, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.10 (m, 1H), 6.81 (t, J=8.0 Hz, 1H), 6.78 (br, 1H), 6.75 (ddd, J=7.4, 2.2, 1.6 Hz, 1H), 1.46 (s, 9H).