Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([OH:14])[CH:5]=1.Cl[Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18].O>C1COCC1>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([O:14][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:5]=1
Reactant: Oc1cc(Br)c2ccccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cc(Br)c2ccccc2c1)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 95.8 %

Procedure:
Sodium hydride (0.38 g, 15.9 mmol) was added portionwise to a solution of 4-bromo-2-naphthol (3.54 g, 15.9 mmol) in THF (50 mL) with stirring at 0° C. under N2. Ater 0.5 h chlorotriisopropylsilane (3.06 g, 15.9 mmol) was added dropwise at 0. The solution was stirred at room temperature for 2 h, poured into water (200 mL), extracted with DCM (dichloromethane) (4×50 mL), dried (MgSO4) and the solvent removed under reduced pressure. The residue was chromatographed on silica using hexanes as eluent. The solvent was removed under reduced pressure to give the title compound (5.78 g, 96%) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:46])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:46])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:28]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1cccc(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)O)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1cccc(OC)c1

Procedure:
To a solution of 90 mg of 4-((S)-4-tert-Butoxycarbonyl-2-{[5-ethoxycarbonylmethoxy-1-(3-methoxy-phenyl)-1H-pyrazole-3-carbonyl]-amino}-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DCM, 0.3 ml of TFA was added at RT. After 4 h 20 ml of toluene was added and the solvents were removed under reduced pressure. The residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid. Yield: 22 mg
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][NH2:6].[N:16]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[C:17]=[O:18].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:5][NH:6][C:17]([NH:16][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[C:22]([CH3:29])[N:23]=[CH:24]2)=[O:18]
Reactant: NCc1ccc(N2CCCCC2)c(F)c1
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(N4CCCCC4)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 3-fluoro-4-(1-piperidinyl)benzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.73 (s, 1H), 9.47 (s, 1H), 8.62 (s, 1H), 8.58 (d, 1H, J=8.4 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.83 (t, 1H, J=8.4 Hz), 7.57 (t, 1H), 7.10 (m, 3H), 4.32 (d, 2H, J=6 Hz), 2.98 (m, 4H), 2.79 (s, 3H), 1.67 (m, 4H), 1.53 (m, 2H); MS (ESI) 393 (M+H)+; Anal. Calcd for C23H25FN4O.1.5HCl: C, 61.78; H, 5.97; N, 12.53. Found: C, 61.40; H, 6.04; N, 12.18.
Reaction SMILES: [SH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[C:23]3[CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:24](O)=[O:25])[CH2:3]1.[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.Cl.CNOC.[F:61][C:62]1[CH:67]=[CH:66][C:65]([Mg]Br)=[CH:64][CH:63]=1>CN(C=O)C.C1COCC1>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]([N:5]3[CH2:6][C@H:2]([SH:1])[CH2:3][C@H:4]3[C:24](=[O:25])[C:65]3[CH:66]=[CH:67][C:62]([F:61])=[CH:63][CH:64]=3)=[O:8])[C:20]3[C:21](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:22]=2[CH:23]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1C[C@@H](S)CN1C(=O)OCc1cccc2c1Cc1ccccc1-2
Reactant: Fc1ccc([Mg]Br)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: CNOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)[C@@H]1C[C@@H](S)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 2 h

Procedure:
Resin derivatized with (2S,4R)-4-sulfanyl-1-(fluorenylmethoxycarbonyl)-pyrrolidine-2-carboxylic acid (9.71 g, 5.73 mmol) above, was treated with DMF (abs. 80 ml), TPTU (3.4 g, 11.46 mmol), DIEA (2.94 ml, 17.2 mmol) for 15 min. The DMF solution was removed under vacuum and the reaction flask was charged with N,O-dimethylhydroxylamine.hydrochloride (1.68 g, 17.2 mmol) in DMF (abs. 80 ml). The reaction mixture was shaken for 2 h and the resin was collected at the filter, washed (3× alternating DMF/isopropanol), DMF. The resin (1.0 g, 0.6 mmol) was washed with THF(abs.2×) under an argon overpressure resuspended in THF (abs. 8 ml) and treated with 4-fluorophenyl magnesiumbromide (1M in THF, 5.9 ml). After 4 h the resin was filtered off and washed with THF. 0.5 N KHSO4 was added and the reaction flask was shaken for 15 min. The resin was further washed DMF, 0.5 N KHSO4, (alternating DMF, MeOH, H2O ), DMF, CH2Cl2, diethyl ether and dried. The resin (0.38 mg) was treated with 40% TFA/CH2Cl2 (10 ml), triisopropylsilane (0.5 ml) for 1 h and the filtrate was collected and concentrated under reduced pressure and the residue was purified by prep.RP-HPLC and the desired fractions were pooled and freeze-dried from acetic acid (10 ml) yielding (2S,4R)-2-(4-fluoro-benzoyl)-4-mercapto-pyrrolidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester MS: 448.3 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[C:6](Cl)(Cl)=[S:7].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[C:33]([NH2:36])[CH:34]=2)[NH:29][C:28](=[O:38])[C:27]=1[C:39]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([CH3:46])[CH:40]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>O.C(Cl)(Cl)Cl>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]1[CH2:23][CH2:24][O:25][C:26]1[C:35]2[C:30](=[CH:31][C:32]([Cl:37])=[C:33]([N:36]=[C:6]=[S:7])[CH:34]=2)[NH:29][C:28](=[O:38])[C:27]=1[C:39]1[CH:40]=[C:41]([CH3:46])[CH:42]=[C:43]([CH3:45])[CH:44]=1)=[O:16])([CH3:11])([CH3:13])[CH3:12]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N=C=S)c(Cl)cc3[nH]c2=O)c1

Procedure:
To a stirred suspension of calcium carbonate (320 mg) and thiophosgene (120 mg) in 10 mL water:chloroform (1:1) at 0° C. was added 2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (450 mg, prepared essentially as described in Example 1) and the mixture stirred at low temperature. After 2 hours the reaction was quenched by the addition of 10% hydrochloric acid and stirring continued until the gas evolution ceased. The mixture was then extracted with chloroform, the combined organics dried over magnesium sulfate and concentrated in vacuo to provide the crude title compound (480 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1.Cl>[OH-].[Na+].O.CCO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1/[CH:1]=[CH:17]/[C:16]([C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: O=Cc1ccccc1O
Reactant: CC(=O)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1O)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a vigorously stirred solution of salicylaldehyde (45 mL, 0.42 mol) in 2.5 M NaOH (330 mL) at 0° C. was added 1-(pyridin-3-yl)ethanone (46.2 mL, 0.422 mol) dropwise over 50 min. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water (150 mL) and EtOH (150 mL). The mixture was acidified with conc. HCl to pH=3. The resulting yellow solid was filtered and dried to give (2E)-3-(2-hydroxyphenyl)-1-pyridin-3-ylprop-2-en-1-one (69.8 g, 73%) which was used without further purification. LCMS: (FA) ES+ 226.2, ES-224.2.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])=[C:9]([C@H:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]([CH3:30])=[CH:7][C:5]=2[N:6]=1.[CH:31]([Sn](CCCC)(CCCC)CCCC)=[CH2:32].[NH4+].[Cl-]>[Cu]I.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.CN(C=O)C>[C:26]([O:25][C@@H:19]([C:9]1[C:8]([CH3:30])=[CH:7][C:5]2[N:6]=[C:2]([CH:31]=[CH2:32])[S:3][C:4]=2[C:10]=1[O:11][S:12]([C:15]([F:18])([F:17])[F:16])(=[O:14])=[O:13])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1OS(=O)(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=Cc1nc2cc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(OS(=O)(=O)C(F)(F)F)c2s1
Temperature: 65 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A microwave vial was charged with CuI (9.4 mg, 49 μmol), Pd(PPh3)4 (29 mg, 25 μmol), and 32 (250 mg, 0.494 mmol). The vial was sealed and placed under a vacuum. The vessel was backfilled with argon and charged with DMF (1.0 mL) followed by vinyl-(tri-n-butyl)tin (173 μL, 0593 mmol). Reaction was stirred at 65° C. for 1 h, then cooled to 23° C. Sat. aq. NH4Cl (40 mL) was added and the reaction was extracted with EtOAc (2×20 mL). Combined organic layers were dried (Na2SO4), filtered, and concentrated. Hexane was added, and the slurry was concentrated again. The residue was treated with PhH and purified by silica gel column chromatography (eluent: Hexanes/Ethyl Acetate) giving 91A (173 mg, 77% yield). 1H-NMR: 400 MHz, (CDCl3) δ: 7.80 (s, 1H), 7.00 (dd, J=18.6, 10.9 Hz, 1H), 6.24 (d, J=18.6 Hz, 1H), 5.82 (d, J=10.9 Hz, 1H), 5.60 (s, 1H), 4.24-4.06 (m, 2H), 2.54 (s, 3H), 1.22 (s, 9H), 1.19 (t, J=6.8 Hz, 3H). 19F-NMR: 376 MHz, (CDCl3) δ: 73.8.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[NH:18][N:17]=[CH:16][C:15]=2[C:19]([OH:21])=O)=[CH:10][CH:9]=1.[CH3:22][CH:23]1[NH:27][CH2:26][C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([OH:28])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[NH:18][N:17]=[CH:16][C:15]=2[C:19]([N:27]2[CH:23]([CH3:22])[CH2:24][C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([OH:28])[CH2:26]2)=[O:21])=[CH:12][CH:13]=1
Reactant: CC1CC(O)(c2ccccc2)CN1
Reactant: O=C(O)c1cn[nH]c1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1CC(O)(c2ccccc2)CN1C(=O)c1cn[nH]c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 20.5 %

Procedure:
Pyridine (13 μL, 0.16 mmol, 4 equ.) was added to a solution of 5-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (8 mg, 0.04 mmol), 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol) and TBTU (15 mg, 0.048 mmol, 1.2 equ.) in DMF (0.3 mL) at rt. The reaction mixture was stirred at 60° C. overnight. The crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (3 mg). MS (ESI, pos. ion) m/z: calcd for C21H20FN3O2: 365.1540, found 365.1541.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=2)=[CH:5][CH:4]=1.[Br:18]Br.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:18][C:11]1[N:10]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:13][C:12]=1[C:14]([F:17])([F:15])[F:16]
Reactant: BrBr
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(Br)c(C(F)(F)F)[nH]2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
To a solution of 7 (5 g, 0.025 mol) in CHCl3 (200 ml) was added dropwise a solution of Br2 (1.3 mol, d=3.1, 4.0 g, 0.25 mol) in 100 ml CHCl3. After the addition, the solution was stirred at room temperature for 5 h, poured onto saturated Na2CO3 solution, and separated. The aqueous layer was extracted with CHCl3 (3 x). The organic layers were dried, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with CHCl3 to yield 4.4 g (65%) of 8. An analytical sample was prepared by crystallization from petroleum ether-CHCl3, m.p. 177°-178° C.
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]([F:42])([F:41])[C:6]1[CH:7]=[C:8]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:9][NH:10][C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]2[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[C:27]([CH3:29])=[CH:28][C:12]1=2.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:42][C:5]([F:4])([F:41])[C:6]1[CH:7]=[C:8]([CH:34]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:36]=1)[CH2:9][N:10]([C:2]#[N:1])[C@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]2[CH:25]=[C:26]([C:30]([F:33])([F:31])[F:32])[C:27]([CH3:29])=[CH:28][C:12]1=2
Reactant: N#CBr
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)(C)C)CCC[C@@H]2N(C#N)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 87.5 %

Procedure:
Add cyanogen bromide (1.21 mL, 6.04 mmol, 5 M solution in acetonitrile) to a solution of (S)-tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.30 g, 4.03 mmol) and diisopropylethylamine (1.05 mL, 6.04 mmol) in tetrahydrofuran (50 mL) at room temperature under nitrogen and heat the mixture at 50° C. for 12 h. Add silica gel to the cooled mixture and remove the solvents under reduced pressure. Purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (2:3), to provide the title compound as a colorless oil (2.10 g, >99%), which is used in the next step without further purification: APCI MS m/z 496 (M+H−Boc)+.
Reaction SMILES: [CH:1](=[C:4]1[CH2:7][CH:6]([OH:8])[CH2:5]1)[CH2:2][CH3:3].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[CH3:9][S:10]([O:8][CH:6]1[CH2:7][C:4](=[CH:1][CH2:2][CH3:3])[CH2:5]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CCC=C1CC(O)C1
Solvent: c1ccncc1
Product: CCC=C1CC(OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of 3-propylidene-1-cyclobutanol (0.344 g, 0.00307 mol) in pyridine (5 mL) was cooled to 0° C. Methanesulfonyl chloride (0.422 g, 0.00369 mol) was added dropwise, keeping the temperature below 2° C. The mixture was stirred for two hours, and then poured into ice water (15 mL) and extracted with ethyl ether (2×10 mL). The combined organic layers were washed with water (3×10 mL). The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give 3-propylidenecyclobutyl methanesulfonate (0.492 g, 0.00221 mol) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][S:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1.Cl.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=2)[C:14]([O:16][CH3:21])=[O:15])=[CH:18][CH:19]=1
Reactant: CO
Reactant: COc1ccc(CSc2cncc(C(=O)O)c2)cc1
Agent: Cl
Product: COC(=O)c1cncc(SCc2ccc(OC)cc2)c1

Procedure:
A solution of 2.02 g of 5-(p-methoxybenzylthio)nicotinic acid in hydrochloric acid-methanol is refluxed. The reaction mixture is concentrated. To the residue is added a mixture of chloroform and water. The mixture is extracted with chloroform. The chloroform layer is dried and evaporated to dryness. The resulting residue is recrystallized from isopropyl ether, giving methyl 5-(p-methoxybenzylthio)nicotinate melting at 72°-74° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:28])[NH:14][C:15](=[O:27])[C:16]=3[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH3:26])[CH:18]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[S:34][C:35]1[NH:36][CH:37]=[CH:38]C=1)CCC>>[CH3:26][N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:16]2[C:15](=[O:27])[NH:14][C:13](=[O:28])[C:12]=2[C:6]2[C:5]3[C:9](=[CH:10][C:2]([C:35]4[S:34][CH:38]=[CH:37][N:36]=4)=[CH:3][CH:4]=3)[N:8]([CH3:11])[CH:7]=2)=[CH:18]1
Reactant: CCCC[Sn](CCCC)(CCCC)Sc1ccc[nH]1
Reactant: Cn1cc(C2=C(c3cn(C)c4cc(Br)ccc34)C(=O)NC2=O)c2ccccc21
Product: Cn1cc(C2=C(c3cn(C)c4cc(-c5nccs5)ccc34)C(=O)NC2=O)c2ccccc21
Yield: 22.8 %

Procedure:
3-(1-Methyl-1H-indol-3-yl)-4-(1-methyl-6-thiazol-2-yl-1H-indol-3-yl)pyrrole-2,5-dione (25 mg, 23%) was prepared from 3-(6-bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-1H-indol-3-yl)-pyrrole-2,5-dione (108 mg, 0.25 mmol) and 2-(tributylstannyl)thioazole (140 mg, 0.375 mmol).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=O)(=O)[CH2:2][CH3:3].C([O-])(=O)C.[NH4+:20].C(O)(=O)C>O>[CH2:2]([C:1]1[O:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:20]=1)[CH3:3]
Reactant: [NH4+]
Reactant: CCC(=O)OCC(=O)c1ccc(O)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc(-c2ccc(O)cc2)co1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.9 %

Procedure:
A mixture of 6.2 parts of 2-(4-hydroxyphenyl)-2-oxoethyl propanoate, 2.7 parts of ammonium acetate and 52.5 parts of acetic acid was stirred for 6 hours at reflux temperature. An additional 2.7 parts of ammonium acetate were added and stirring was continued for 5 hours at reflux temperature and overnight at room temperature. The reaction mixture was poured into water and the precipitate was filtered off, yielding a first fraction of product. The aqueous layer was extracted with methylbenzene. The extract was dried, filtered and then combined with the first product fraction. The whole was dried, filtered and evaporated, yielding 3.8 parts (66.9%) of 4-(2-ethyl-4-oxazolyl)phenol (interm. 12).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([NH2:26])[C:17]1=[C:16]2[CH3:27].O>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]1[CH2:22][CH2:23][CH2:24][CH:25]([NH:26][CH:1]=[O:3])[C:17]1=[C:16]2[CH3:27]
Reactant: COc1ccc2c(c1)c(C)c1n2CCCC1N
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(C)c1n2CCCC1NC=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of formic acid (6 mL) and acetic anhydride (12 mL) was heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-2-methoxy-10-methylpyrido[1,2-a]indol-9-amine (5.8 g, 25.2 mmol) in dry tetrahydrofuran (60 mL) was added upon cooling to the resultant mixed anhydride. The reaction mixture was stirred at 25° C. overnight, poured into water (100 mL), and extracted with ether (3×70 mL). The combined extracts were washed successively with 5% hydrochloric acid (80 mL), 5% aqueous sodium bicarbonate (100 mL), and water (100 mL). The ethereal solution was dried over MgSO4, filtered, and evaporated. The solid residue was crystallized from ether-hexane to give 5.4 g (83%) of the title formamide, m.p. 130°-132° C. as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[N:4](C2CCCCO2)[N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Cl:30][C:31]([F:55])([F:54])[O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:53])[C:41]2[CH:46]=[C:45](I)[C:44]([N:48]3[CH2:51][CH:50]([OH:52])[CH2:49]3)=[N:43][CH:42]=2)=[CH:35][CH:34]=1.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.CC#N.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.CCOC(C)=O>[Cl:30][C:31]([F:54])([F:55])[O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:53])[C:41]2[CH:46]=[C:45]([C:5]3[NH:4][N:3]=[C:2]([CH3:1])[CH:6]=3)[C:44]([N:48]3[CH2:49][CH:50]([OH:52])[CH2:51]3)=[N:43][CH:42]=2)=[CH:35][CH:34]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC(O)C2)c(I)c1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C2CCCCO2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC(O)C2)[nH]n1
Temperature: 80 °C
Reaction time: 19 h

Procedure:
3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (252 mg, 0.646 mmol), K3PO4 (206 mg, 0.968 mmol) and Pd(PPh3)4 (18.65 mg, 0.016 mmol) were added to N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxyazetidin-1-yl)-5-iodonicotinamide (Stage 88.1, 160 mg, 0.323 mmol) was suspended in toluene (2 mL) in a. vial, which was sealed, purged with argon and stirred at 80° C. for 19 h. The RM was treated with EtOAc (60 mL), washed with an aq. sat. NaHCO3 solution (20 mL) and brine (2×20 mL), dried over Na2SO4, and the solvent was evaporated off under reduced pressure. The residue was dissolved in MeOH (3 mL) and filtered through a SPE PL-Thiol cartridge (StratoSphere™, 500 mg, 1.5 mmol), filtered and the filtrate was evaporated off under reduced pressure to give a residue which was purified by flash chromatography (RediSep®Silica gel column, 40 g, DCM/MeOH 95:5), dissolved in DCM (2 mL), treated with TFA (0.554 mL, 7.19 mmol) and stirred at RT for 2 h. The dark yellow RM was treated with EtOAc, washed with aq. sat. NaHCO3 solution and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 24 g, DCM/MeOH 9:1). The fractions containing pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in MeCN (2 mL), sonicated and then stirred at RT for 1 h. The resulting suspension was filtered, washed with MeCN (3 mL) and dried to afford the title product as a white solid. HPLC (Condition 7) tR=5.648 min, UPLC-MS (Condition 8) tR=0.93 min, m/z=450.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 3H) 3.52-3.60 (m, 2H) 3.92-4.01 (m, 2H) 4.34-4.44 (m, 1H) 5.51 (br. s, 1H) 6.16 (s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.84-7.90 (m, 2H) 8.04 (d, J=2.35 Hz, 1H) 8.71 (d, J=1.96 Hz, 1H) 10.21 (s, 1H) 12.65 (br. s, 1H).