Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])#[N:4].O.Cl>C1COCC1>[NH2:4][CH2:3][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH3:11])[C:6]=1[CH3:12]
Reactant: Cc1nccc(C#N)c1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nccc(CN)c1C
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
To a solution of NaBH4 (65 g, 0.28 mol) in THF (150 ml) was added dropwise BF3-diethyletherate (119.2 g, 0.84 mol) at 0° C. The reaction mixture was stirred for 20 minutes at 23° C. before adding dropwise a solution of 4-cyano-2,3-dimethylpyridine (18.5 g, 0.14 mol, prepared according to J. Heterocycl. Chem. 27 (6), 1990, 1751) in THF (100 ml). The resulting reaction mixture was refluxed for 6 h. Subsequently the reaction mixture was slowly hydrolyzed with water (200 ml) and the pH-value was adjusted to pH 2 with aqueous hydrochloric acid (10% strength). The resulting reaction mixture was refluxed for another 2 hours. Subsequently the reaction mixture was poured onto water and extracted with MTBE. The aqueous layer was adjusted to pH 14 with an aqueous sodium hydroxide solution (50% strength) and extracted once more with DCM. The combined organic layers were dried and the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, MTBE) to yield 4-(aminomethyl)-2,3-dimethylpyridine as an oily substance (16.5 g). 1H-NMR (CDCl3): δ=1.7 (s, 2H), 2.3 (s, 3H), 2.5 (s, 3H), 3.9 (s, 2H), 7.15 (d, 1H) and 8.3 ppm (d, 2H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1.[CH:16]([N:29]1[CH2:32][C:31](=[O:33])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH:16]([N:29]1[CH2:32][C:31]([C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH:7]=2)([OH:33])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Brc1coc2ccccc12
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2cc3ccccc3o2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (2.23 mL, 5.58 mmol) was added dropwise to a solution of 3-bromobenzofuran (1.0 g, 5.08 mmol) in THF (35 mL) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. and then a solution of 1-benzhydrylazetidin-3-one (1.2 g, 5.08 mmol, as prepared in step 1 of example FAB270) in THF (10 mL) was added dropwise at the same temperature. The mixture was allowed to warm back to room temperature overnight. Water (50 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel using petroleum ether/dichloromethane (50:50 to 0:100) as eluent. The title compound was obtained as a yellow solid (230 mg, 13%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[S:8]([CH3:11])(=O)=O)#[N:2].[Na].[Cl:24][C:25]1[CH:26]=[N:27][CH:28]=[C:29]([Cl:32])C=1S>>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[S:8][C:11]1[C:25]([Cl:24])=[CH:26][N:27]=[CH:28][C:29]=1[Cl:32])#[N:2]
Reactant: Sc1c(Cl)cncc1Cl
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccccc1
Agent: [Na]
Product: CCOC(=O)c1sc(Sc2c(Cl)cncc2Cl)c(C#N)c1-c1ccccc1

Procedure:
Prepared according to the procedure described for step C of example 18 from Ethyl 4-cyano-5-(methylsulfonyl)-3-phenylthiophene-2-carboxylate (0.3 g, 0.89 mmol) from above and 3,5-dichloropyridine-4-thiol sodium salt (0.18 g, 1.0 mmol) at 90° C. for over night. The title product was obtained as a white solid. The crude product was used as such for the next step transformation. MS m/z: 434.98, 436.98 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])=[CH:15][CH:14]=3)[C:7](=[O:12])[CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.O1CCCC1.O.C([O-])=O.[NH4+]>CO>[O:12]=[C:7]1[N:6]([C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])=[CH:17][CH:18]=2)[C:5]2[CH:29]=[CH:30][CH:2]=[CH:3][C:4]=2[NH:10][C:9](=[O:11])[CH2:8]1
Reactant: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccc(Cl)cc2N1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)c3ccccc3)cc2)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.7 %

Procedure:
N-[4-(7-Chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide (28 mg, 0.06 mmol) obtained in Example 169 was dissolved in methanol (0.6 mL), tetrahydrofuran (0.6 mL), and water (0.6 mL), the solution was added with ammonium formate (38 mg, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was filtered through Cerite, and the solvent was evaporated under reduced pressure. The obtained residue was added with water, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=100/1) to obtain the title compound (19 mg, yield 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[C:4]2[C:10]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl>C(O)(C(F)(F)F)=O.C(Cl)Cl.CCOCC>[ClH:1].[NH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:17]([C:3]2[C:2]([Cl:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12]([CH:14]4[CH2:15][CH2:16]4)=[O:13])[C:4]=23)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: N[C@@H]1CCCN(c2c(Cl)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Yield: 138.1 %

Procedure:
A solution of (R)-tert-butyl 1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (462 mg, 1.06 mmol) in neat TFA (4 mL) was stirred at room temperature for 30 minutes and concentrated in vacuo. The oily residue obtained was dissolved in CH2Cl2 (1 mL) and treated with 2M HCl in ether (4 mL). The resulting precipitate was evaporated from CH3CN (4×10 mL) to provide (R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (271 mg, 63% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.79 (d, 1H), 9.65 (s, 1H), 8.25 (br s, 3H), 8.11 (s, 1H), 7.48 (d, 1H), 3.53-3.48 (m, 1H), 3.44-3.31 (m, 2H), 3.23-3.11 (m, 2H), 2.13-2.08 (m, 1H), 1.89-1.80 (m, 2H), 1.75-1.70 (m, 1H), 1.54-1.45 (m, 1H0, 0.82 (d, 4H). LCMS (APCI+) m/z 334 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:11]([O:13][C:14](=[O:19])[C:15](Br)([CH3:17])[CH3:16])C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:11][O:13][C:14](=[O:19])[C:15]([O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 110 °C

Procedure:
A mixture of 5-chloro-2-hydroxy-benzaldehyde (7 g, 45 mmol), 2-bromo-2-methyl-propionic acid ethyl ester (10.4 g, 58 mmol), K2CO3 (18.6 g, 135 mmol) and KI (0.97 g, 5.8 mmol) in DMF (20 mL) was heated at 110° C. for 3 h. Then the mixture was filtered and the filtrate was concentrated. The residue was used into next step reaction without further purification (7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([C:16]([O:18]CC)=O)[C:11](OCC)=[O:12].C(N(CC)CC)C.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.[OH-].[Na+]>O>[OH:18][C:16]1[C:10]([C:3]2[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][C:4]=2[F:9])=[C:11]([OH:12])[N:30]2[N:31]=[CH:32][N:33]=[C:29]2[N:28]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1c(F)cc(F)cc1F
Reactant: Nc1nc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: Oc1nc2ncnn2c(O)c1-c1c(F)cc(F)cc1F
Temperature: 180 °C
Reaction time: 6 h

Procedure:
A mixture of 22 mmol of diethyl 2-(2,4,6-trifluorophenyl)malonate, 24 mmol of triethylamine and 22 mmol of 3-amino-1,2,4-triazole was heated with stirring at 180° C. for 6 hours. The reaction mixture was then cooled to 50° C., admixed with a solution of 2.2 g of sodium hydroxide in 25 ml of water and stirred for 30 minutes. The aqueous phase was washed with ether and then acidified with conc. hydrochloric acid. The precipitated colorless solid was filtered off, washed with water and diisopropyl ether and dried. The yield of the title compound was 85% (m.p.: 200-201° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([NH2:49])(=[O:48])=[O:47])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O.N>>[F:1][C:2]1[CH:3]=[C:4]([NH:45][S:46]([NH2:49])(=[O:47])=[O:48])[CH:5]=[C:6]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(F)cc(NS(N)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cc(F)cc(NS(N)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 58.1 %

Procedure:
N-[3-Fluoro-5-(4-{[(1S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl]amino}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl]sulfamide (46 mg, 0.06 mmol) was treated with trifluoroacetic acid (2.0 ml, 26.0 mmol) and a solution of ammonia (7N in methanol, 10 ml, 70.0 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 5% dichloromethane-methanol) to obtain 20 mg (57% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([O:28][Si](C)(C)C(C)(C)C(C)C)[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1.[F-].[NH4+].[ClH:43]>CO.C(OCC)(=O)C.C(OCC)C>[ClH:43].[NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([OH:28])[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](c1nc(CN)no1)CSC2
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](c1nc(CN)no1)CSC2

Procedure:
(R)-4-(3-Aminomethyl-1,2,4-oxadiazol-5-yl)-16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-I 1,2,5-benzoxathiaazacyclotetradecin-12-one was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1. The resulting product was dissolved in ethyl acetate. Upon the addition of a 3N solution of hydrochloric acid in diethyl ether, a precipitate formed which was isolated to yield (R)-4-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-16-hydroxy-14-methoxy-13-methyl-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one hydrochloride as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][CH2:39][O:40][CH3:41])=[N:35][CH:36]=1.O>CN(C=O)C>[CH3:41][O:40][CH2:39][CH2:38][O:37][C:34]1[N:35]=[CH:36][C:31]([O:1][C:2]2[CH:3]=[C:4]([CH3:23])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:6]([CH3:8])[CH:7]=2)=[CH:32][CH:33]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COCCOc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Oc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 105 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a solution of N-(4-(4-Hydroxy-2,6-dimethylphenyl)-thiazol-2-yl)isonicotinamide (5-3, 0.98 g, 3.0 mmol) in DMF (10 mL) were added cesium carbonate (1.95 g, 6.0 mmol, 2.0 equiv) and Cu (58.5 mg, 0.90 mmol, 0.3 equiv). The mixture was stirred at 100-110° C. for 1.0 h and added with 5-bromo-2-(2-methoxyethoxy)pyridine (17-2, 1.04 g, 4.5 mmol). The solution heated at 130° C. for 24 h. The reaction mixture was added with water (40 mL) and extracted with EtOAc. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=3/1-1/3) to give 17 (0.94 g) in 66% yield: 1H NMR (500 MHz, CDCl3) δ 8.81 (d, 2 H), 7.93 (d, 1 H), 7.88 (d, 2 H), 7.32 (m, 1 H), 6.82 (d, 2 H), 6.57 (s, 2 H), 4.45 (t, 2 H), 3.75 (t, 2 H), 3.44 (s, 3 H), 1.99 (s, 6 H), ESI-MS=m/z 477.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([N:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:15]=[C:16]([Cl:21])[CH:17]=[C:18]([Cl:20])[CH:19]=2)[C:9](=[O:10])[CH2:8]1)=[O:6])[CH3:3].C1(S(OC)(=O)=[O:33])C2C(=CC=CC=2)C=CC=1.[Na].C=O.S([O-])(OCCCCCCCCCCCC)(=O)=O.[Na+]>>[CH3:3][CH:2]([NH:4][C:5]([N:7]1[C:12](=[O:13])[N:11]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:9](=[O:10])[CH2:8]1)=[O:6])[CH3:1].[OH2:33]
Reactant: COS(=O)(=O)c1cccc2ccccc12
Agent: C=O
Agent: CC(C)NC(=O)N1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Agent: CCCCCCCCCCCCOS(=O)(=O)[O-]
Product: O

Procedure:
2% benziothiazolinone, 73% iprodione, 5% sodium methyl naphthalene sulfonate-formaldehyde condensate, 4% sodium lignosulfonate, 3% sodium dodecyl sulfate, complemented to 100% with diatomite.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:25]1[C:34]([OH:35])=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.ClC1C=CC=C2C=1C(O)(C1C(O)=CC3OCCC=3C=1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:25]1[C:34]([OH:35])=[CH:33][C:28]3[O:29][CH2:30][CH2:31][O:32][C:27]=3[CH:26]=1)[C:5](=[O:24])[N:6]2[CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C1(O)c1cc2c(cc1O)OCCO2
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCC2
Product: O=C1C(c2cc3c(cc2O)OCCO3)c2c(Br)cccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 4C, and making non-critical variations using 4-bromo-1-(diphenylmethyl)-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 4-chloro-1-(diphenylmethyl)-3-hydroxy-3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1,3-dihydro-2H-indol-2-one, 4-bromo-1-(diphenylmethyl)-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (86%): as a yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.42-7.28 (m, 10H), 6.98-6.87 (m, 3H), 6.68 (s, 1H), 6.33 (d, J=7.6 Hz, 1H), 6.16 (s, 1H), 4.22-4.16 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:8][O:9][C:4]=2[CH:3]=1.N1CCCCC1.Cl[CH2:25][CH:26]1[O:28][CH2:27]1>>[O:28]1[CH:26]([CH2:25][O:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:8][O:9][C:4]=3[CH:3]=2)[CH2:27]1
Reactant: ClCC1CO1
Reactant: Oc1ccc2c(c1)OCC(c1ccccc1)C2
Solvent: C1CCNCC1
Product: c1ccc(C2COc3cc(OCC4CO4)ccc3C2)cc1

Procedure:
17 g 7-hydroxy-3-phenyl-3,4-dihydro-2H-1-benzopyrane, 0.1 cm3 piperidine and 100 cm3 1-chloro-2,3-epoxypropane were stirred for 6 hours at a temperature of 90° C. The solution was evaporated under reduced pressure, the residue was dissolved in 150 cm3 benzene and the obtained solution was extracted twice with 25--25 cm3 saturated sodium carbonate solution. The benzene phase was separated from the precipitated resin, clarificated with charcoal, filtered and evaporated. Crystallizing the residue from methanol, 15 g pure crystalline 1,2-epoxy-3-(3-phenyl-3,4-dihydro-2H-1-benzopyrane-7-yloxy)-propane was obtained (m.p. 117°-119° C.).
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.C([O:11][C:12](=[O:23])[CH:13](P(OCC)(OCC)=O)[CH3:14])C.[H-].[Na+].[OH-].[K+]>C(O)C>[C:2]12([CH:13]([CH3:14])[C:12]([OH:23])=[O:11])[O:8][CH:5]([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=C1CCC(O)CC1
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C(=O)O)C12CCC(CC1)O2

Procedure:
The title compound was prepared by standard Wittig-Horner reaction from 4-hydroxy-cyclohexanone, 2-(diethoxy-phosphoryl)-propionic acid ethyl ester and sodium hydride (J. Boutagy, R. Thomas, Chem. Rev. 1974, 74, 87-99) and subsequent saponification with potassium hydroxide in ethanol. After recrystallization from n-heptane, the title compound was obtained as white solid. EI-MS: m/e=170(M+), 1H-NMR (90 MHz, CDCl3, TMS):δ 1.3 (d, J=8 Hz, 3H, Me), 1.7 (m, 8H, CH2), 3.0 (q, J=8 Hz, 1H, CH-Me), 4.6 (t, J=4.5 Hz, 1H, CH—O), 7.2 (s, 1H, COOH), mp 61-62° C., bp 120° C. (0.008 mbar).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[S:7][C:6]=2[CH:5]=[CH:4][C:3]=1[N+:15]([O-])=O.CCOC(C)=O>C(O)C.[Pd]>[NH2:15][C:3]1[CH:4]=[CH:5][C:6]2[S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1c([N+](=O)[O-])ccc2sc3ccccc3c12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(N)ccc2sc3ccccc3c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-Methyl-2-nitrodibenzothiophene (Method 11; 0.855 g, 3.52 mmol) was stirred in ethanol (50 ml) and EtOAc (50 ml) under an argon atmosphere. 10% Palladium on carbon (0.09 g) was added to the solution and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 3 h. The mixture was filtered through diatomaceous earth and washed with EtOAc before the filtrate was evaporated in vacuo. The crude product was purified by flash chromatography eluting with 50% DCM/iso-hexane-DCM. Evaporation of the appropriate fractions left the product as a colourless solid. NMR: 8.39 (m, 1H), 7.92 (m, 1H), 7.50 (m, 1H), 7.42 (m, 2H), 6.92 (d, 1H), 4.98 (brs, 2H), 2.60 (s, 3H); m/z 215.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([OH:25])=O)[N:21]=1)=[CH:5]2.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:17]1[S:18][CH2:19][C@@H:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[N:21]=1)=[CH:5]2
Reactant: O=C(O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: C1COCCN1
Product: O=C(C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1)N1CCOCC1

Procedure:
[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid prepared in Example 4 and morpholine were reacted according to the same procedure as Step B of Preparation 101 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[C:10](OC(=O)C)=[CH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.O>CCO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)Oc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Fc1ccc(-n2ccc3cc(Cl)ccc32)cc1
Temperature: 25 °C

Procedure:
1-(4-flourophenyl)-3-acetoxy-5-chloroindole (100.0 g, 0.33 mol) was dissolved in 1000 mL EtOH. During the next hour sodium borohydride pellets (18.7 g, 1.5 eq.) were added batchwise at reflux. The reaction mixture was stirred over night at reflux and cooled to room temperature. Concentrated HCl (appr. 50 mL until pH 1) was added and the reaction mixture was stirred at room temperature for 1 hour. 200 mL demineralized water was added, and the resulting suspension was filtrated. The filter cake was washed with further 50 mL water and 10 mL EtOH. The product was dried over night in vacuum at 50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].CO.[BH4-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][N:17]3[C:10](=[CH:11][C:12]4[CH2:13][C:14]([CH3:21])([CH3:20])[CH2:15][C:16]=43)[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24]
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Reaction time: 1 h
Yield: 77.6 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 4-chloro-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridine-3-carbaldehyde 108a (9.0 g, 26.1 mmol, 1.0 eq.), methanol (50 mL), dichloromethane (30 mL), and NaBH4 (5.95 g, 156.6 mmol, 5.0 eq.) at 0° C. The reaction mixture was stirred for 1 h. After the reaction was completed, the reaction was quenched with water and concentrated under reduced pressure. The residue was extracted with dichloromethane. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:4 ethyl acetate/petroleum ether to afford 199c as a white solid (7.0 g, 77%). MS-ESI: [M+H]+ 345.9.
Reaction SMILES: [CH:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20](OS(C(F)(F)F)(=O)=O)=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:33][CH:34]([CH3:43])[CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:39]/B(O)O>O1CCCC1>[CH:1]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:22]=[CH:21][C:20]([CH:39]=[CH:38][CH2:37][CH2:36][CH2:35][CH:34]([OH:33])[CH3:43])=[CH:19][N:18]=2)=[CH:13][CH:12]=1)=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC=Cc1ccc(-c2ncc(OS(=O)(=O)C(F)(F)F)cn2)cc1
Reactant: CC(O)CCC/C=C/B(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCC=Cc1ccc(-c2ncc(C=CCCCC(C)O)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
After replacing the inner atmosphere of a four-necked flask equipped with a stirring device and a thermometer with nitrogen gas, the flask was charged with 1.0 g (2.26 mmol) of the 2-{4-(1-decenyl)-phenyl}-5-trifluoromethylsulfonyloxypyrimidine obtained above. Then, 0.01 g (0.008 mmol) of tetrakis-triphenylphosphine-palladium, 0.27 g (6.78 mmol) of sodium hydroxide and 20 ml of tetrahydrofuran were added thereto. Further, 19.5 ml of a solution prepared by dissolving 3.39 mmol of E-6-hydroxy-1-heptenyldihydroxyborane, prepared in the same manner as in Example 4, in tetrahydrofuran was dropwise added thereto at room temperature. The whole mixture was heated under reflux with stirring for 8 hours, and cooled to room temperature. After extraction with 30 ml of toluene, the organic layer was twice washed with each 10 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to obtain 0.63 g (yield 69%) of 2-{4-(1-decenyl)-phenyl}-5-(6-hydroxy-1-heptenyl)-pyrimidine.