Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5](=O)[C:6]([CH3:14])([C:8]1[O:12][N:11]=[C:10]([CH3:13])[N:9]=1)[CH3:7].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]2[N:42]=[C:5]([C:6]([CH3:14])([C:8]3[O:12][N:11]=[C:10]([CH3:13])[N:9]=3)[CH3:7])[CH:4]=[CH:3][N:41]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: Cc1noc(C(C)(C)C(=O)C=CN(C)C)n1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2nccc(C(C)(C)c3nc(C)no3)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from crude 1-dimethylamino-4-methyl-4-(3-methyl-[1,2,4]oxadiazol-5-yl)-pent-1-en-3-one (140 mg, 0.6 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (186 mg, 0.5 mmol) using in analogous manner the procedure described in example 39b). Obtained as a pale-yellow solid (31 mg, 13%).
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH2:16])[C:8]=32)=[N:3]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH:16][C:24](=[O:26])[CH3:25])[C:8]=32)=[N:3]1
Reactant: Cn1cc2c3c(ccc2n1)CCC3=CCN
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCC=C1CCc2ccc3nn(C)cc3c21
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
2-(2-Methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (400 mg, 1.88 mmol) was dissolved in tetrahydrofuran (19 mL), triethylamine (287 μL, 2.06 mmol) and acetic anhydride (195 μL, 2.06 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (393 mg, yield 82%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Br[CH2:10][CH2:11][CH2:12][OH:13]>C1(C)C(C)=CC=CC=1>[CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[CH2:10][CH2:11][CH2:12][OH:13]
Reactant: OCCCBr
Reactant: C[C@@H]1CCC[C@H](C)N1
Solvent: Cc1ccccc1C
Product: C[C@@H]1CCC[C@H](C)N1CCCO

Procedure:
A stirred solution of 460 g. of cis-2,6-dimethylpiperidine in 300 ml. of xylene is treated with 278 g. of 3-bromopropanol over a period of 15 minutes. The mixture is stirred and heated at reflux for 2 hours, then allowed to cool while stirring for 16 hours. The mixture is filtered and the filtrate evaporated at reduced pressure. The residue is distilled at reduced pressure to give cis-2,6-dimethyl-1-piperidinepropanol; b.p. 147°-149° C./25 mm.
Reaction SMILES: [N:1]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4][CH2:3][CH:2]1[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].IC.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].N>C1COCC1>[CH3:27][C:2]1([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])[CH2:3][CH2:4][N:1]1[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: O=C(OCc1ccccc1)C1CCN1C(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(C(=O)OCc2ccccc2)CCN1C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A solution of Example 22A (325 mg, 1 mmol) and iodomethane (0.12 ml, 2.0 mmol) in THF (5 mL) was treated with NaN(TMS)2 in THF (1.0 M, 2 mL, 2.0 mmol) at −70° C. under nitrogen. The temperature of the cooling bath was slowly raised to −20° C. within 1 h and the mixture was stirred at the same temperature for additional 2 h. After quenching with water, the mixture was partitioned between water and EtOAc. The organic phase was washed with water and concentrated. The residue was purified on flash column chromatograph to give Example 22B. (250 mg, 77% yield). MS (DCI/NH3) m/z 340 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[F:12][C:13]([F:18])([F:17])[CH2:14][Mg]Br>>[CH3:3][C:1]([CH3:4])([O:5][C:6]([NH:7][CH2:8][CH:9]([OH:10])[CH2:14][C:13]([F:18])([F:17])[F:12])=[O:11])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: FC(F)(F)C[Mg]Br
Product: CC(C)(C)OC(=O)NCC(O)CC(F)(F)F

Procedure:
t-Butyl-N-(2-oxoethyl)carbamate is treated with 1,1,1-trifluoroethyl magnesium bromide to give (R/S)-1-[(1,1-dimethylethoxycarbonyl)]amino-4,4,4-trifluoro-2-butanol. The procedures and methods used in this synthesis are the same as those listed in Example 3, except that (R/S)-1-[(1,1-dimethylethoxy)carbonyl]amino-4,4,4-trifluoro-2-butanol is used instead of (S)-1-[(benzyloxycarbonyl)amino]-2-propanol, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]#[N:14])[CH:9]=[N:10]2)=[CH:5][CH:4]=1.N[C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>ClC1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[O:18][CH2:17][C:16]([CH3:20])([CH3:19])[N:14]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(C#N)cnc2c1
Reactant: CC(C)(N)CO
Solvent: Clc1ccccc1
Product: COc1ccc2cc(C3=NC(C)(C)CO3)cnc2c1

Procedure:
A solution of 7-methoxy-3-cyanoquinoline reported in Tetrahedron Letters 39, 1998, 4013-4016 (1.84 g, 10 mmol) and 2-amino-2-methyl-1-propanol (0.90 g, 10 mmol) in chlorobenzene under nitrogen atmosphere is refluxed for 2 days. The solvent is evaporated under vacuum to afford the desired compound
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][CH:17]=2)[CH:6]=[C:7](C2C=CC=CC=2)[CH:8]=1.C1C(=O)N([I:25])C(=O)C1.C(OCC)(=O)C.O>C(#N)C>[I:25][C:17]1[CH:16]=[N:15][N:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=12
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(-c2ccccc2)cn2nccc12
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccn2ncc(I)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
4-methoxy-6-phenylpyrazolo[1,5-a]pyridine (17, 200 mg, 0.892 mmol) and NIS (241 mg, 1.070 mmol) were dissolved in acetonitrile (20 mL) and stirred at room temperature for 1 hour. The reaction was then poured into ethyl acetate and water, extracted organics, washed 1N NaOH and brine, dried with magnesium sulfate, filtered, and concentrated to give a white solid. This was purified by column chromatography (0-30% ethyl acetate in hexanes, linear gradient) and to yield 3-iodo-4-methoxypyrazolo[1,5-a]pyridine (18, 310 mg, 0.885 mmol, 99% yield). MS APCI: [M+H]+ m/z 351.2.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:63]([CH3:66])([CH3:65])[CH3:64])[C:13]([N:15]1[C@H:19]([C:20](=[O:32])[NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)[CH2:18][C@H:17]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][C@@H:38]([C:50](=[O:62])[NH:51][C@H:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:55][CH2:54][CH2:53]4)[N:39](C(OC(C)(C)C)=O)[CH2:40]3)=[CH:35][CH:34]=2)[CH2:16]1)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCCl>[CH3:64][C:63]([CH3:66])([CH3:65])[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13](=[O:14])[N:15]1[CH2:16][C@@H:17]([C:33]2[CH:42]=[C:41]3[C:36]([CH2:37][C@@H:38]([C:50](=[O:62])[NH:51][C@H:52]4[C:61]5[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=5)[CH2:55][CH2:54][CH2:53]4)[NH:39][CH2:40]3)=[CH:35][CH:34]=2)[CH2:18][C@H:19]1[C:20](=[O:32])[NH:21][C@H:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc([C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)[C@@H](NC(=O)OCc4ccccc4)C(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H](c2ccc3c(c2)CN[C@H](C(=O)N[C@@H]2CCCc4ccccc42)C3)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a solution of (S)-tert-butyl 7-((3R,5S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dimethylbutanoyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.44 g, 0.49 mmol) in DCE (5 mL) was added TFA (1.2 mL, 15.6 mmol). The reaction mixture was stirred at rt for 2 h and concentrated in vacuo. The residue was basified with sat. aq. NaHCO3 solution. The resulting mixture was extracted with EtOAc (2×) and the organic layer was separated, washed with brine and dried over MgSO4. The filtrate was concentrated in vacuo to give the title compound as a light yellow solid (0.35 g, 91%). MS (ESI+) m/z 796.5 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:17]=[CH:16][C:15](Br)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5].[CH3:19][O:20][CH2:21][CH2:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1>>[NH2:1][C:2]1[N:17]=[CH:16][C:15]([C:26]2[CH:25]=[N:24][N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH:27]=2)=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[CH3:13])=[O:5]
Reactant: Cc1cnccc1NC(=O)c1cc(Br)cnc1N
Reactant: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COCCn1cc(-c2cnc(N)c(C(=O)Nc3ccncc3C)c2)cn1

Procedure:
Reaction of 2-amino-5-bromo-N-(3-methyl-pyridin-4-yl)-nicotinamide with 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole gives the compound “A22”; HPLC/MS: 1.07 min, [M+H]=353;
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1>>[CH3:26][C:27]([OH:44])([CH3:43])[CH2:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:25]=[CH:24][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4CC(F)(F)F)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 193. MS(ESI+) 491.1. 1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.27 (d, J=8.3, 1H), 8.18 (s, 1H), 7.96 (s, 1H), 7.45 (dd, J=8.3, 1.8, 1H), 7.31 (d, J=1.7, 1H), 5.86 (q, J=8.7, 2H), 4.71 (s, 1H), 4.39 (t, J=5.0, 2H), 4.03 (s, 2H), 3.47 (t, J=5.0, 2H), 1.10 (s, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][C:9]=2[CH2:22][N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:10][C:9]=2[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH2:27][CH2:28]2)=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(OS(=O)(=O)C(F)(F)F)ccc2-c2ccc(Cl)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(N3CCOCC3)ccc2-c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A suspension of EXAMPLE 198B (500 mg), morpholine (80 mg), palladium (II) acetate (22 mg), biphenyl-2-yldi-tert-butylphosphine (50 mg) and cesium carbonate (427 mg) in anhydrous tetrahydrofuran (6 mL) was heated at 50° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash column purification with 30-50% ethyl acetate/hexane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(C(=NO)N)[CH2:29][CH2:28]1.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH:27]4[CH2:29][CH2:28]4)[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(C4CC4)no3)c2[C@@H]2CCCN12
Reaction time: 0.33 h

Procedure:
8.10 g (22 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole are dissolved in 30 ml of N,N-dimethylformamide, whereupon the solution is treated with 2.50 g (25 mmol) of cyclopropanecarboxamidoxime and the mixture is heated to 70° for 4.5 hours. The reaction mixture is then poured into 350 ml of water, stirred for 20 minutes and the precipitated product is filtered off under suction. The residue is washed with water and dried. The above residue is dissolved in 30 ml of glacial acetic acid and stirred at 115° for 2.5 hours. The reaction mixture is subsequently evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. After evaporation of the eluate there is obtained (S)-8-chloro-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 213°-214°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.[Br:12][CH2:13][C:14]([CH2:16]Br)=O.O>CN(C=O)C>[Br:12][CH2:13][C:14]1[N:11]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[S:10][CH:16]=1
Reactant: NC(=S)Nc1ccc(Br)cn1
Reactant: O=C(CBr)CBr
Solvent: O
Solvent: CN(C)C=O
Product: BrCc1csc(Nc2ccc(Br)cn2)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 16 %

Procedure:
(5-Bromo-pyridine-2-yl)-thiourea (2.5 mmol) is dissolved in DMF (5 ml) and 1,3-dibromacetone (1 eq.) is added and stirred 2 h at 70° C. After cooling to RT, the reaction solution is poured into water and the resulting precipitate is filtered, washed with water and dried 16 h in vacuo at 40° C. After column chromatography (ethyl acetate/methanol) (4-bromomethyl-thiazole-2-yl)-(5-bromo-pyridine-2-yl)-amine is obtained as a colourless powder with a yield of 16%. HPLC (method C): 1.92 min; LC-MS (method A): 1.977 min, 347.95 (M+H+); 1H-NMR (DMSO-d6, 300 MHz): δ [ppm] 11.583 (s, 1H), 8.391 (d, 1H, J=2.4 Hz), 7.902 (dd, 1H, J=2.4 Hz, J=8.9 Hz), 7.119 (s, 1H), 7.023 (d, 1H, J=8.9 Hz), 4.622 (s, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[NH:27]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]1>C(Cl)Cl.CO>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:27]3[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[CH2:29][CH2:28]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(CN3CCS(=O)(=O)CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and DIPEA (2 eq) were dissolved in DCM/MeOH (5:1 v:v) under N2 and thiomorpholine 1,1-dioxide (2 eq) was added portion wise. The resulting solution was stirred at room temperature for 16 h. After this time, the reaction was complete. The solvent was evaporated. The compound was extracted with EtOAc and water, washed with brine and dried over anhydrous MgSO4. Organic layers were filtered and evaporated. The final compound was isolated without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]1[CH:14]=[C:15]2[C:21]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)=[CH:20][N:19]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:16]2=[N:17][CH:18]=1)(C(C)(C)C)(C)C>CO.[OH-].[OH-].[Pd+2]>[CH3:27][N:25]1[CH:26]=[C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:14]=3)[N:19]([S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:29])=[O:30])[CH:20]=2)[CH:23]=[N:24]1
Reactant: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(/C=C/CCO[Si](C)(C)C(C)(C)C)cc23)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncc(CCCCO)cc23)cn1
Reaction time: 43 h

Procedure:
A mixture of olefin 65 (198 mg, 0.38 mmol) and moist Pd(OH)2 on carbon (96 mg of catalyst containing 20% wt Pd) in MeOH (6 mL) was stirred vigorously under H2 for 43 h. The catalyst was removed by filtration through a pad of Celite. The pad was washed sequentially with MeOH, CH2Cl2 and AcOH and the combined filtrates were concentrated to afford azaindole 66 as brown oil that was used directly without purification in the next step; 1H NMR (400 MHz; CDCl3) δ 1.55-1.76 (m, 4H), 2.71 (t, J=7.7 Hz, 2H), 3.64 (t, J=6.4 Hz, 2H), 3.97 (s, 3H), 7.43-7.47 (m, 2H), 7.52-7.56 (m, 1H), 7.64 (s, 1H), 7.71 (s, 1H), 7.73-7.75 (m, 2H), 8.16-8.18 (m, 2H), 8.27 (d, J=1.9 Hz, 1H).
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])[N:28]=4)[N:25]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[C:37]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[C:27]([C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])[N:28]=4)[N:25]=3)[CH2:15][CH2:16]2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(CCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Yield: 63 %

Procedure:
905 mg of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate dihydrochloride was dissolved in 6 ml of ethanol; 5.9 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 4.5 by the addition of 1 N hydrochloric acid. The mixture was crystallized by the addition of acetone, washed with acetone and dried to yield 476 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15](=[O:20])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH3:27][Mg]Cl>CCCCCCC.C1COCC1>[F:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[CH:6][C:5]([C:11]2[CH:19]=[C:18]3[C:14]([C:15]([OH:20])([CH3:27])[CH2:16][CH2:17]3)=[CH:13][C:12]=2[C:21]([O:23][CH3:24])=[O:22])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2=O
Reactant: C[Mg]Cl
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(cc1-c1cc(C(C)C)c(F)cc1OC)CCC2(C)O
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-oxoindane-5-carboxylate (45.9 mg, 0.129 mmol) in heptane (1 mL) and THF (1 mL) at −20° C. under N2, was added dropwise 3N MeMgCl in THF (86 uL, 0.258 mmol). The reaction mixture was stirred at −20° C. for 2 h. The mixture was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to give methyl 6-(4-fluoro-5-isopropyl-2-methoxyphenyl)-3-hydroxy-3-methylindane-5-carboxylate. LCMS calc.=395.2; found=394.9 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 7.89 (s, 1H); 7.20 (s, 1H); 7.09 (d, J=8.6 Hz, 1H); 6.62 (d, J=12.1 Hz, 1H); 3.72 (s, 3H); 3.70 (s, 3H); 3.28-3.20 (m, 1H); 3.15-3.09 (m, 1H); 2.96-2.90 (m, 1H); 2.36-2.24 (m, 2H); 1.91 (br s, 1H); 1.66 (s, 3H); 1.30 (d, J=6.9 Hz, 6H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:9]=[N:10][NH:11][CH:12]=1.CS(O[CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]1)(=O)=O>CN(C=O)C.O>[Br:7][C:8]1[CH:9]=[N:10][N:11]([CH:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:12]=1
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCC(n2cc(Br)cn2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Cesium carbonate (1.96 g, 6 mmol) and 4-bromopyrazole (321 mg, 2.2 mmol) were added to a solution of ethyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (0.50 g, 2 mmol) in DMF (10 mL). The mixture was stirred at 80° C. for 16 hours. Upon cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to give ethyl 4-(4-bromo-1H-pyrazol-1-yl)cyclohexanecarboxylate. MS ESI calc'd. for C12H18BrN2O2 [M+H]+ 301 and 303. found 301 and 303. 1H NMR (400 MHz, CDCl3): δ 7.45 (s, 1H), 7.44 (s, 1H), 4.23 (q, J=7.2 Hz, 2H), 2.46-2.38 (m, 1H), 2.26-2.18 (m, 4H), 2.06-1.98 (m, 2H), 1.86-1.78 (m, 3H), 1.36 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[O:24][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)C1CCCc2c1c1c(O)cccc1n2Cc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 80 mg (0.25 mmol) of 9-benzyl-4-carbamoyl-5-hydroxy-1,2,3,4-tetrahydrocarbazole in 2.5 mL of DMF was treated with 61 mg (0.30 mmol) of Cs2CO3 followed by 26 mg (0.30 mmol) of methyl bromoacetate. The mixture was stirred at room temperature until tlc indicated complete consumption of starting material (2 hours). The reaction was diluted with H2O (10 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (3×20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (SiO2; 2.5% MeOH in CH2Cl2) to afford 50 mg (0.13 mmol; 51%) of [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid, methyl ester as an oil. 1H NMR (CDCl3) δ 7.33-7.21 (m, 3H), 7.05-6.98 (m, 3H), 6.98 (d, 1H, J=7.4 Hz), 6.46 (br s, 1H), 6.37 (d, 1H, J=7.7 Hz), 5.52 (br s, 1H), 5.23 (d, 1H, J=4.9 Hz), 4.79-4.70 (m, 2H), 4.20-4.15 (m, 1H), 3.81 (s, 3H), 2.79-2.69 (m, 1H), 2.63-2.49 (m, 1H), 2.43-2.35 (m, 1H), 2.25-2.09 (m, 1H), and 1.99-1.78 (m, 2H). IR (CHCl3, cm−1) 1759, 1670, 1497, 1453, 1440, and 1132. MS (ES) m/e 393 (M+1).