Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(CC1C=C2C(=CC=1)NC(C1C(Cl)=CC=CC=1Cl)CC2SC1C=CC=CC=1)C(OC)=O)(=[O:8])C1C=CC=CC=1.[Cl:41][C:42]1[CH:80]=[CH:79][CH:78]=[C:77]([Cl:81])[C:43]=1[CH2:44][NH:45][CH:46]([CH2:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[NH:58][CH:57]([C:62]1[C:67]([Cl:68])=[CH:66][CH:65]=[CH:64][C:63]=1[Cl:69])[CH2:56][CH:55]2[S:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:47]([O:49][CH3:50])=[O:48].ClC1C=CC=C(Cl)C=1C(NC(CC1C=C2C(=CC=1)NC(C1C(OC)=CC=CC=1OC)CC2SC1C=CC=CC=1)C(OC)=O)=O.ClC1C=CC=C(Cl)C=1C(NC(CC1C=C2C(=CC=1)NC(C1SC=CN=1)CC2SC1C=CC=CC=1)C(OC)=O)=O.ClC1C=CC=C(Cl)C=1C(NC(CC1C=C2C(=CC=1)NC(C1C(Cl)=CN=CC=1Cl)CC2SC1C=CC=CC=1)C(OC)=O)=O.ClC1C=CC=C(Cl)C=1C(NC(CC1C=C2C(=CC=1)NC(C1C=CN=CC=1)CC2SC1C=CC=CC=1)C(OC)=O)=O>>[Cl:81][C:77]1[CH:78]=[CH:79][CH:80]=[C:42]([Cl:41])[C:43]=1[C:44]([NH:45][CH:46]([CH2:51][C:52]1[CH:53]=[C:54]2[C:59](=[CH:60][CH:61]=1)[NH:58][CH:57]([C:62]1[C:63]([Cl:69])=[CH:64][CH:65]=[CH:66][C:67]=1[Cl:68])[CH2:56][CH:55]2[S:70][C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)[C:47]([O:49][CH3:50])=[O:48])=[O:8]
Reactant: COC(=O)C(Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1c(Cl)cccc1Cl)N2)NC(=O)c1ccccc1
Reactant: COC(=O)C(Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1c(Cl)cccc1Cl)N2)NCc1c(Cl)cccc1Cl
Agent: COC(=O)C(Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1c(Cl)cncc1Cl)N2)NC(=O)c1c(Cl)cccc1Cl
Agent: COC(=O)C(Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1c(OC)cccc1OC)N2)NC(=O)c1c(Cl)cccc1Cl
Agent: COC(=O)C(Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1ccncc1)N2)NC(=O)c1c(Cl)cccc1Cl
Product: COC(=O)C(Cc1ccc2c(c1)C(Sc1ccccc1)CC(c1c(Cl)cccc1Cl)N2)NC(=O)c1c(Cl)cccc1Cl

Procedure:
Methyl 2-(benzoylamino)-3-[2-(2,6-dichlorophenyl)-4-(phenylsulfanyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 9a, methyl 2-[(2,6-dichlorobenzyl)amino]-3-[2-(2,6-dichlorophenyl)-4-(phenylsulfanyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 9b (MS (MH+): 645/647/649), methyl 2-[(2,6-dichlorobenzoyl)amino]-3-[2-(2,6-dimethoxyphenyl)-4-(phenylsulfanyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 9c (MS (MH+): 651/653/655), methyl 2-[(2,6-dichlorobenzoyl)amino]-3-[4-(phenylsulfanyl)-2-(1,3-thiazol-2-yl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 9d (MS (MH+): 596/598/600), methyl 2-[(2,6-dichlorobenzoyl)amino]-3-[2-(3,5-dichloro-4-pyridinyl)-4-(phenylsulfanyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 9e (MS (MH+): 658/660/662) and methyl 2-[(2,6-dichlorobenzoyl)amino]-3-[4-(phenylsulfanyl)-2-(4-pyridinyl)-1,2,3,4-tetrahydro-6-quinolinyl]propanoate 9f (MS (MH+): 590/592/594) can be synthesized according to the same method.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C([C@H]1[C@H](N)C2[CH:30]=[CH:31][S:32]C=2CC1)CC>>[CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[CH:30]=[CH:31][S:32][C:19]=3[CH2:18][CH2:17][C@H:16]2[CH2:15][CH2:14][CH3:13])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCC[C@@H]1CCc2sccc2[C@H]1N
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: CCC[C@@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting trans-5-propyl-4,5,6,7-tetrahydro-1-benzothiophen-4-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.66, 7.08, 6.44, 5.19, 4.46, 2.82, 2.68-2.52, 2.03, 1.94, 1.78, 1.53-1.48, 1.26, 0.92; HRMS (FAB) calcd for C19H27N3S+H 330.2004, found 330.1993.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].C1C(=O)N([Br:25])C(=O)C1>C1COCC1>[CH2:1]([O:3][C:4](=[O:15])[C:5]([Br:25])([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(CC(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
To an ice-cooled solution of 2-isobutylmalonic acid diethyl ester (3.21 g, 14.8 mmol) in THF (50 mL) was added portionwise sodium hydride (1.19 g, 60% in oil, 29.7 mmol). The mixture was stirred in the ice bath for 15 min, and then at RT for 15 min. The suspension was re-cooled in the ice bath and NBS (2.9 g, 16.3 mmol) was added over 5 min. The mixture was stirred in the ice bath for 10 min, and then at RT for 30 min. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-6% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.828 g, 88%). 1H NMR (CDCl3, 300 MHz): δ 4.27 & 4.26 (4H, 2 q, J=7.1 Hz), 2.26 (2H, d, J=6.2 Hz) 1.95 (1H, nonet, J=6.5 Hz), 1.29 (6H, t, J=7.1 Hz), 0.94 (6H, d, J=6.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[NH:23]1[CH:27]=[N:26][N:25]=[N:24]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:27]5[NH:26][N:25]=[N:24][N:23]=5)[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: c1nnn[nH]1
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccn(-c3nnn[nH]3)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with 1H tetrazole under Buchwald reaction conditions to provide the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:43])[CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]3[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:29]3)=[N:17][C:16]=2[N:15]([CH3:42])[C:13]1=[O:14])([OH:3])=O.C(=O)([O-])[O-].[NH4+].[NH4+].[N:50]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.F[B-](F)(F)F.OC1C2N=NNC=2C=CC=1>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[OH:43][C:10]1([CH2:11][N:12]2[C:21](=[O:22])[C:20]3[N:19]([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:18]([N:28]4[CH2:33][CH2:32][CH2:31][CH:30]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:29]4)=[N:17][C:16]=3[N:15]([CH3:42])[C:13]2=[O:14])[C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1](=[O:3])[NH:50]1
Reactant: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1C(=O)O)c(=O)n2C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC1(O)NC(=O)c3ccccc31)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 250 mg of 1-[2-(2-carboxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-[3-(tert.-butyloxycarbonyl-amino)-piperidin-1-yl]-xanthine, 404 mg of ammonium carbonate, 135 mg of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate, 57 mg of hydroxybenzotriazole and 59 μl of triethylamine in 3 ml of tetrahydrofuran is stirred for eight hours at ambient temperature. For working up the reaction mixture is diluted with 30 ml of ethyl acetate and washed with 10% citric acid solution, 10% potassium carbonate solution and saturated sodium chloride solution. The organic phase is evaporated down and chromatographed through a silica gel column with methylene chloride/methanol (98:2 to 80:20).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:23]2[CH2:25][C@H:24]2[C:26]([O:28]CC)=[O:27])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH2:17][N:16]([C:21]([C@@H:23]2[CH2:25][C@H:24]2[C:26]([OH:28])=[O:27])=[O:22])[CH2:15]3)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)N1Cc2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)Nc2ccc3c(c2)CN(C(=O)[C@@H]2C[C@H]2C(=O)O)C3)nc1Cl
Yield: 67.8 %

Procedure:
Ethyl trans(±)-2-[(5-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-1,3-dihydro-2H-isoindol-2-yl)carbonyl]cyclopropanecarboxylate obtained in Example (93a) (0.11 g, 0.26 mmol) was dissolved in methanol (5 mL) and dichloromethane (2 mL). The solution was subjected to the same operation as in Example (91d) using a 2 N aqueous lithium hydroxide solution (2 mL, 4 mmol), to obtain 71 mg of the title compound as a light brown solid (69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([OH:9])=[O:8].[CH2:12](Cl)Cl.CO.C[Si](C=[N+]=[N-])(C)C>CCOCC>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:10]=1[CH3:11])[C:7]([O:9][CH3:12])=[O:8]
Reactant: Cc1c(Br)cncc1C(=O)O
Reactant: ClCCl
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cncc(Br)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 5-bromo-4-methylnicotinic acid (223.4 mg, 1.034 mmol) in methylene chloride (3.0 mL, 47 mmol) and methanol (3.0 mL, 74 mmol) was added 2.0 M of trimethylsilyldiazomethane in ether (0.70 mL). The reaction mixture was stirred at room temperature for one hour, and then 2.0 M of trimethylsilyldiazomethane in ether (0.50 mL) was added. After an additional two hours, the crude reaction mixture was evaporated in vacuo to yield 237.2 mg (100%) of methyl 5-bromo-4-methylnicotinate which was carried forward without further purification. LCMS (ESI): M+H=230.2; 1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.82 (s, 1H), 3.89 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:11][C:12]1[CH:13]=[C:14]([S:18]([CH3:26])(=[N:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:19])[CH:15]=[CH:16][CH:17]=1>C(#N)C>[CH2:24]([O:23][C:21]([N:20]=[S:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:5]2[N:4]=[C:3]([S:9][CH3:10])[C:2]([Br:1])=[CH:7][N:6]=2)[CH:13]=1)([CH3:26])=[O:19])=[O:22])[CH3:25]
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(N)c1
Reactant: CSc1nc(Cl)ncc1Br
Solvent: CC#N
Product: CCOC(=O)N=S(C)(=O)c1cccc(Nc2ncc(Br)c(SC)n2)c1
Yield: 59.9 %

Procedure:
Intermediate 13 was prepared in analogy to GP 2 by reaction of 2.15 g of Intermediate 12 (4.5 mmol, 1 eq.) and 1.09 g of Intermediate 5 (4.5 mmol, 1 eq.) to yield (after crystallization from acetonitrile) 1.2 g of Intermediate 13 (60% yield).
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].[BH4-].[Na+]>CO.C(O)(C)C>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[CH:19]([OH:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)C(O)CC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.1 %

Procedure:
To a stirred solution of 17-allyl- 1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)1-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (300 mg, 0.374 mmol) in 9 ml MeOH was added dropwise at RT a solution of NaBH4 (0.12 mmol) in 2 ml isopropanol. After stirring at RT for 15 minutes the reaction was quenched by pouring into 1.5 ml acetic acid in ice and the mixture was extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with sat. NaHCO3 (1×50 ml) and water (1×50 ml) and dried over MgSO4. Evaporation of solvent gave 320 mg of crude product which was purified by prep TLC (10% i-PrOH/CH2Cl2) to give 127 mg (42% yield) of the title compound (with NMR and mass spectra consistent with the structure).
Reaction SMILES: C(OC([N:8]1[C:11]2([CH2:14][N:13]([C:15](=[O:26])[NH:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>>[C:20]1([CH2:19][CH2:18][CH2:17][NH:16][C:15]([N:13]2[CH2:12][C:11]3([N:8]([S:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[C:28]([F:27])([F:39])[F:40])(=[O:37])=[O:36])[CH2:9][CH2:10]3)[CH2:14]2)=[O:26])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NCCCc1ccccc1)C2
Product: O=C(NCCCc1ccccc1)N1CC2(CCN2S(=O)(=O)c2ccccc2C(F)(F)F)C1

Procedure:
In analogy to the experimental procedure of example 6b) 6-(3-phenyl-propylcarbamoyl)-1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of tert-butyl 1-(2,4-dichlorobenzylcarbamoyl)-1,6-diazaspiro[3.3]heptane-6-carboxylate was converted using 2-trifluoromethylbenzene-1-sulfonyl chloride instead of 4-chlorobenzene-1-sulfonyl chloride into the title compound which was obtained as an off-white solid (38 mg, 25%). MS m/e: 468 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[CH:14][N:13]=2
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cccnc2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1-c1nc2cccnc2o1

Procedure:
A mixture of 700 mg. of 2-(2-nitrophenyl)oxazolo[ 5,4-b]pyridine in 50 ml. of ethanol was hydrogenated over 150 mg. of 5% palladium on carbon catalyst. The catalyst was removed by filtration and the solvent was concentrated to dryness. The residue was recrystallized from chloroform-petroleum ether to give 2-(2-aminophenyl)oxazolo[ 5,4-b]pyridine, m.p. 142°-144° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH:12]=[C:13]2[CH2:18][CH2:17][C:16]([CH2:22][CH2:23][CH2:24][CH3:25])([N:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)=[CH:2]1>C1(C)C=CC=CC=1.ClCCl>[CH3:20][N:19]([CH3:21])[C:16]1([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:18][C:13]2([C:2]3[NH:1][C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[C:3]=3[CH2:10][CH2:11][CH2:12]2)[CH2:14][CH2:15]1
Reactant: CCCCC1(N(C)C)CCC(=CCCc2c[nH]c3ccccc23)CC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC2(CCCc3c2[nH]c2ccccc32)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
p-toluol sulphonic acid (323 mg, 1.7 mmol) was added to a solution 4-[3-(1H-indol-3-yl)propylidene]-1-butyl-N,N-dimethylcyclohexanamine (289 mg, 0.85 mmol) in absolute toluol (10 mL) and stirred for 18 h at 100° C. The reaction solution was then diluted with dichloromethane (30 mL) and washed with 1 N sodium carbonate solution (2×30 mL), water and saturated sodium chloride solution (30 mL each) one after the other, dried with sodium sulphate and concentrated to low volume in a vacuum. The raw product (272 mg) was mixed with methanol (100 mL) and stirred overnight at room temperature, during which very little precipitate was formed (light-coloured solid). The 1H-NMR spectrum and the LC-MS data showed that this concerned two isomers, and the 1H-NMR spectrum revealed that these were present in a ratio of approx. 1:1 and olefin side-products were present at most in very small quantity. The reaction solution was concentrated to low volume in a vacuum (259 mg, 90%). The diastereomer mixture was separated by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].[Li]CCCC.[O:16]=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:16])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:21][CH2:22]2)=[C:3]([CH2:9][OH:10])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OCc1cc(Cl)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2CO)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
A solution of (2-bromo-5-chlorophenyl)methanol (1.48 g, 6.68 mmol) in anhydrous THF (30 mL) was cooled to −78° C. and treated with the dropwise addition of n-BuLi (1.6 M in hexanes) (8.77 mL, 14.03 mmol), and the mixture was stirred for 30 minutes at −78° C., during which a thick white precipitate was observed. The dianion was treated with the dropwise addition of a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.465 g, 7.35 mmol) in THF (10 mL), and the mixture was stirred for 1 hour at −78° C., during which a yellow homogeneous solution was observed, then allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride and the mixture was extracted 3× with ethyl acetate. The combined organic phases were washed with water and brine, then dried over sodium sulfate and concentrated in-vacuo. The residue was split into two equal fractions, and each was purified over a 40 g silica gel column via ISCO, eluting with a 10-100% EtOAc/Hexanes gradient over 15 minutes. The fractions from each run which contained the desired product were combined to yield the title compound (1.4 g, 4.10 mmol, 61.3% yield) as a colorless foam. MS (ESI+)=268, (M+H-tBuOH)+.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@H:52]2[CH2:56][O:55][CH2:54][C@H:53]2[OH:57])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]>>[CH2:2]([O:57][C@H:53]1[CH2:54][O:55][CH2:56][C@H:52]1[NH:51][C:35]1[C:34]([CH2:32][CH3:33])=[N:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])=[C:37]([CH2:49][CH3:50])[N:36]=1)[CH3:3]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@H]1COC[C@H]1O
Product: CCO[C@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting of cis-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (liq.) 2972, 2935, 2874, 1609, 1564, 1481, 1395, 1294, 1243, 1204, 1160, 1123, 1077, 1069, 1058 cm−1; OAMS supporting ions at: ESI+ 386.2; MS (EI) m/z 385 (M+); HRMS (FAB) calcd for C22H31N3O3+H1 386.2443, found 386.2457. Anal. Calcd for C22H31N3O3: C, 68.54; H, 8.11; N, 10.90. Found: C, 68.22; H, 8.05; N, 10.76.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]CC2C(OC)=CC(OC)=CC=2OC)O)[CH:6]=[CH:7][CH:8]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>CCCCCC.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]
Reactant: COc1cccc(C(O)c2ccccc2SCc2c(OC)cc(OC)cc2OC)c1
Agent: CC[SiH](CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(Cc2ccccc2S)c1
Yield: 76.5 %

Procedure:
0.288 g (3-methoxyphenyl)(2-(2,4,6-trimethoxybenzylthio)phenyl)methanol (K) (0.68 mmol) was treated with a solution of triethylsilane:TFA:DCM 0.3 ml:1 ml:10 ml. The mixture was stirred overnight at ambient temperature before the addition of water. The mixture was extracted with DCM, brine, dried over magnesium sulfate and concentrated. Flash silica chromatography (hexane:ethyl acetate 90:10) afforded 0.12 g product (0.52 mmol, 77% yield).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:26])[NH:17][C:18]3[C:23]/2=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)/[CH:9]=1.[CH3:27][O:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[F:25])[NH:17][C:16](=[O:26])/[C:15]/2=[C:10]1\[CH:9]=[C:8]([C:34]2[CH:35]=[CH:36][C:31]([C:29]([O:28][CH3:27])=[O:30])=[CH:32][CH:33]=2)[C:12]([CH3:14])([CH3:13])[O:11]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1Br
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cc1
Temperature: 86 °C

Procedure:
To 10 mL of 1,4-dioxane, was added the following reagents: (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-5,6-difluoro-1,3-dihydro-2H-indol-2-one (250 mg, 0.73 mmol), 4-methoxycarbonylphenylboronic acid (158 mg, 0.88 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 2M Na2CO3 aqueous solution (1.5 mL, 3.0 mmol). The mixture was heated at 86° C. under N2 for 2 hours, cooled to room temperature and poured into 100 mL of water. The brown precipitates were filtered, washed with water and dried to give the crude product. Purification through silica gel column with 1-2% MeOH/CHCl3 led to methyl 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoate as orange/red solid. Yield: 112 mg, 39%.
Reaction SMILES: [NH4+]=S.[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([N+:13]([O-])=O)[C:7]=2[S:6][CH:5]=1>C(O)C.O>[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[CH:11]=[C:12]([NH2:13])[C:7]=2[S:6][CH:5]=1
Reactant: Cc1csc2c([N+](=O)[O-])cc([N+](=O)[O-])cc12
Solvent: CCO
Solvent: O
Product: Cc1csc2c(N)cc([N+](=O)[O-])cc12
Temperature: 0 °C

Procedure:
453 ml of a 20% strength ammonium sulphide solution (1.33 moles of (NH4)2S) are added dropwise to a suspension of 0.4 mole of 3-methyl-5,7-dinitrobenzothiophene in 1,400 ml of ethanol at 55°-60° C. in the course of 45 minutes, and the mixture is then heated at the boiling point for 15 minutes. The mixture is then diluted with 1,400 ml of water and cooled to 0° C. and the crystalline product is filtered off with suction. For purification, the crystals are dissolved in methylene chloride and the solution is filtered over a silica gel column (eluting agent: methylene chloride/cyclohexane 9:11). The substance obtained from the combined eluates is recrystallised from isopropanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].N#N.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:25]([NH:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[C@@H:18]([CH3:24])OS(C)(=O)=O)=[O:15])([CH3:12])([CH3:11])[CH3:10]>O.ClCCCl>[C:9]([O:13][C:14]([NH:16][C@H:17]1[C@H:18]([CH3:24])[N:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]1=[O:26])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OC(C)(C)C)C(=O)NOCc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Yield: 60.5 %

Procedure:
Potassium carbonate (200g) was dissolved in 300ml of water, 1.5 liters of 1,2-dichloroethane was added, and the mixture was refluxed. A suspension of 178 g of N2 -(t-Butyloxycarbonyl)-O-(methylsulfonyl)-N-(phenylmethoxy)-L-threonineamide in 1.2-dichloroethane was added and the mixture was refluxed for 2 hours. The layers were cooled and the organic layer was evaporated, redissolved in ethyl acetate, washed twice with water, dried (MgSO4) and evaporated again. The oily residue crystallized on treatment with petroleum ether, yielding 76.7 g of the title compound, melting point 78° C.