Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=5)=[CH:32][C:27]4=[N:26][CH:25]=3)=[CH:20][CH:19]=2)=[O:15])[N:8]([CH2:10][CH2:11][OH:12])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:13][C:14]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:28]4[CH:29]=[CH:30][C:31]([C:33]5[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=5)=[CH:32][C:27]4=[N:26][CH:25]=3)=[CH:22][CH:23]=2)=[O:15])[N:8]([CH2:10][CH2:11][O:12][S:51]([CH3:50])(=[O:53])=[O:52])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCO)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(-c3cnc4cc(-c5ccc(S(C)(=O)=O)cc5)ccn34)cc2)n(CCOS(C)(=O)=O)n1
Yield: 97 %

Procedure:
In a round bottomed flask dissolve 1-[5-tert-butyl-2-(2-hydroxy-ethyl)-2H-pyrazol-3-yl]-3-{4-[7-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridin-3-yl]-benzyl}-urea (0.2 g, 0.34 mmol) and triethyl amine (0.48 mL, 10 equiv.) in DCM (20 mL) under N2. Add methanesulfonyl chloride (0.13 mL, 4.8 equiv.) dropwise and stir the reaction at room temperature for 15 minutes. Load the crude reaction directly onto silica gel and purify (EtOAc to 5% MeOH: DCM) to give a yellow solid (0.22 g, 97%). MS (ES), m/z 665 (M+1).
Reaction SMILES: [F:1][C:2]1([F:19])[C:6]2[N:7]([CH2:14][C:15]([OH:17])=O)[N:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:5]=2[C@H:4]2[CH2:18][C@@H:3]12.Cl.[NH2:21][C@H:22]([C:32]1[C:37]([C:38]2[CH:39]=[CH:40][C:41]([F:47])=[C:42]([CH:46]=2)[C:43]([NH2:45])=[O:44])=[CH:36][C:35]([N:48]2[C:56](=[O:57])[C:55]3[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:49]2=[O:58])=[CH:34][N:33]=1)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:19][C:2]1([F:1])[C:6]2[N:7]([CH2:14][C:15]([NH:21][C@H:22]([C:32]3[C:37]([C:38]4[CH:39]=[CH:40][C:41]([F:47])=[C:42]([CH:46]=4)[C:43]([NH2:45])=[O:44])=[CH:36][C:35]([N:48]4[C:49](=[O:58])[C:50]5[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=5)[C:56]4=[O:57])=[CH:34][N:33]=3)[CH2:23][C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)=[O:17])[N:8]=[C:9]([C:10]([F:11])([F:13])[F:12])[C:5]=2[C@H:4]2[CH2:18][C@@H:3]12
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1C(F)(F)[C@@H]1C[C@H]21
Reactant: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@@H](N)Cc2cc(F)cc(F)c2)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cc(-c2cc(N3C(=O)c4ccccc4C3=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc1F
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid (13 mg, 0.045 mmol), (S)-5-(2-(1-amino-2-(3,5-difluorophenyl)ethyl)-5-(1,3-dioxoisoindolin-2-yl)pyridin-3-yl)-2-fluorobenzamide hydrochloride (30I, 25 mg, 0.045 mmol) and HATU (21 mg, 0.054 mmol) were dissolved in 10 mL DMF, cooled to 0° C., then N,N-diisopropylethylamine (0.032 mL, 0.18 mmol) was added dropwise. The reaction mixture was allowed to stir at 0° C. for 5 min, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with NaHCO3 (sat'd aq.) and brine. After dried over MgSO4, it was filtered and concentrated. The residue was purified by RP-HPLC eluting with acetonitrile/H2O (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, CD3OD): δ 8.87 (s, 1H), 7.98 (m, 2H), 7.88 (m, 2H), 7.76 (d, 1H), 7.54-7.30 (m, 2H), 7.24 (dd, 1H), 6.67 (t, 1H), 6.39 (m, 2H), 5.51-5.26 (m, 1H), 4.88 (s, 2H), 3.18-2.98 (m, 2H), 2.63-2.41 (m, 2H), 1.40 (m, 1H), 1.11 (m, 1H). MS (m/z) 781.03 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[CH:11](=[O:15])[CH2:12][CH2:13][CH3:14].[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH:11]([OH:15])[CH2:12][CH2:13][CH3:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCCC=O
Reactant: N#Cc1cc(I)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(O)c1ccc(Br)c(C#N)c1
Temperature: -8 °C
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
A round bottom flask was charged with the 2-bromo-5-iodobenzonitrile (2.00 g, 6.49 mmol) and THF (9 mL). Solution cooled down to −8° C. (ice/brine bath). Turbo Grignard 1.3M in THF (5.50 mL, 7.14 mmol) is then added in one portion and the reaction stirred for 15 minutes at −8° C. Butyraldehyde (0.698 μL, 7.79 mmol) is then charged in another flask and the preformed anion is added over the aldehyde/THF (4 mL) via canula and then, reaction allowed to warmed at room temperature overnight under magnetic stirring. Ammonium chloride (sat. aq.) added to the mixture. Extracted 3× with Ethyl Acetate. Combined organic layers washed with water (1×), with brine (1×), dried over sodium sulfate, filtered and concentrated to afford the crude material. Purification by silica gel flash chromatography (Ethyl Acetate/Heptane) provide the title compound as a yellow oil (1.33 g, 80.6%). 1H NMR (400 MHz, DMSO-d6) δ 0.83 (t, J=7.41 Hz, 3H) 1.18-1.34 (m, 2H) 1.46-1.57 (m, 2H) 4.52-4.58 (m, 1H) 5.37 (d, J=4.88 Hz, 1H) 7.56 (dd, J=8.58, 1.95 Hz, 1H) 7.79 (d, J=8.39 Hz, 1H) 7.81 (d, J=2.15 Hz, 1H); MS (M): 255.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]2([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=3)[O:16][CH2:15]2)[CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:24].[C:25]([O-:28])(=[O:27])[CH3:26].[Na+]>C(O)(=O)C>[C:25]([O:28][CH2:15][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[N:18]=1)([OH:16])[CH2:13][N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=1)(=[O:9])=[O:10])[CH3:12])(=[O:27])[CH3:26]
Reactant: Cc1cc(S(=O)(=O)N(C)CC2(c3cccc(Cl)n3)CO2)ccc1Cl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(O)(CN(C)S(=O)(=O)c1ccc(Cl)c(C)c1)c1cccc(Cl)n1
Temperature: 100 °C
Reaction time: 12 h
Yield: 72.6 %

Procedure:
A mixture of 7.0 g of 1-[N-(4-chloro-3-methylbenzenesulfonyl)-N-methylamino]-2-(6-chloropyridin-2-yl)-2,3-epoxypropane, 3.70 g of anhydrous sodium acetate and 60 ml of acetic acid was stirred at 100° C. for 12 hours. The reaction mixture was concentrated under a reduced pressure and 100 ml of water was added thereto. The mixture was extracted with ethyl acetate, subsequently washed with water, saturated aqueous solution of sodium bicarbonate and saturated saline solution in that order, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluted with ethyl acetate - n-hexane 1:3 ) to obtain 5.87 g of the objective compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH3:23].Cl[CH2:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>CN1CCCC1=O>[CH2:20]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[CH2:25][CH2:26][CH2:27][S:28]2(=[O:30])=[O:29])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCN1CCCS1(=O)=O
Yield: 11.3 %

Procedure:
Using the general method of Example 266 except that 1-methyl-2-pyrrolidinone was used in place of dichloromethane, 1-(4-aminobutyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (5.0 g, 16.0 mmol) was reacted with 3-chloropropanesulfonyl choride (2.83 g, 16.0 mmol) to provide 0.75 g of 2-butyl-1-[4-(1,1-dioxidoisothiazolidin-2-yl)butyl]-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 173.0-176.0° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C(O)(=O)C(C)=C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](OCC)OCC
Agent: C=C(C)C(=O)O
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 64.7 %

Procedure:
200 mg of styrene, 320 mg of triethoxysilane, and 370 mg of toluene were placed in a glass reaction tube and 0.0014 ml of methacrylic acid was added. Next, 0.002 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.4 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 66.3%, phenethyltriethoxysilane was produced at a yield of 64.7%, and the yield of (α-methylbenzyl)triethoxysilane was 1.0%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C>[Cl:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]([C:13]4[C:14]([F:27])=[C:15]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=4[F:19])=[O:12])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)nc1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)nc4)cc23)c1F
Reaction time: 0.27 h

Procedure:
Propane-1-sulfonic acid [3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (56, 10 mg, 0.022 mmol) was weighed into a 5 mL microwave vial and combined with 6-chloro-pyridine-3-boronic acid (72, 4.4 mg, 0.028 mmol), followed by the addition of 600 μL of acetonitrile and 500 μL of 1M potassium carbonate and a spatula tip (˜1 mg) of [1,1″-bis(diphenylphosphino)-ferrocene]dichloropalladium(II). The reaction mixture was irradiated in a microwave at 160° C. for 5 minutes. The solution was neutralized with 100 μL of acetic acid and all material was transferred to a 4 mL vial and the solvents were removed under vacuum. The crude material was dissolved in 400 μL of dimtheylsulfoxide and purified by reverse phase HPLC, eluting with 0.1% trifluoroacetic acid in water and 0.1% trifluoroacetic acid in acetonitrile, 20-100% acetonitrile over 16 minutes at 6 mL per minute. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound. MS (ESI) [M+H+]+=491.1.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[C:31]([CH3:39])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[C:31]([CH3:39])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1ccc(C(F)(F)F)c2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(F)(F)F)c2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 51.9 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methyl-7-trifluoromethylbenzothiazole (116 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 94 mg (52%) of the title compound as an amorphous foam. mp 50°-54°. FDMS: m/e=476.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.[I-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:22]=[C:23]([CH2:24][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:27][CH:28]=1
Reactant: FC(F)(F)c1cccc(CCl)c1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C(F)(F)F)c2)CCCC1=O
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
40% Methanolic Triton B (2.18 mL, 4.8 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (973 mg, 4.0 mM) in 10 mL of DMF at −10° C. After 30 minutes, 3-(trifluoromethyl)benzyl chloride (1.53 g, 6.0 mM) and sodium iodide (900 mg, 6.0 mM) were added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, 1 N HCl, H2O, sat NaHCO3, and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and dried in vacuo. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.02 g (63%) of the 9-[(3-trifluoromethylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan solid. 1H NMR (CDCl3) δ7.6 (d, 1H, J=8 Hz), 7.45-7.2 (m, 5H), 7.0 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.05 (s, 3H), 2.85 (t, 2H, J=6 Hz), 2.6 (t, 2H, J=6 Hz), and 2.2 (m, 2H). IR (KBr, cm−1) 1727 and 1652. MS (ES) m/e 400, 402.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1.[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17])=[C:6]([Cl:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1c(Cl)ccnc1Br
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1c(Cl)ccnc1Br
Temperature: 15 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 160b (20 g, 90.0 mmol), tert-butyldimethylchlorosilane (17.6 g, 117 mmol) and imidazole (12.2 g, 180 mmol) in N,N-dimethylformamide (300 mL) was stirred at 15° C. for 12 h. See FIG. 5. TLC (petroleum ether:ethyl acetate=3:1) showed that the starting material was completely consumed. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×2). The organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with petroleum ether:ethyl acetate=20:1) to afford 2-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-chloropyridine 160c (30 g, 99%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Cl[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:41]([CH3:42])=[CH:40][C:39]([C:43]6[N:44]([CH3:49])[CH:45]=[C:46]([CH3:48])[N:47]=6)=[CH:38][C:37]=5[CH3:50])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cn(C)c(-c2cc(C)c(Cl)c(C)c2)n1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6nc(C)cn6C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-(4-chloro-3,5-dimethyl-phenyl)-1,4-dimethyl-imidazole following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 7): tR=0.98 min; Mass spectrum (ESI+): m/z=541 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][S:5][CH:6]=1.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11]C(C)=O>>[C:7]([C:3]1[C:2]([CH2:11][C:10]([O:16][CH3:17])=[O:15])=[CH:6][S:5][CH:4]=1)([OH:9])=[O:8]
Reactant: COC(=O)CC(C)=O
Reactant: O=C(O)c1cscc1Br
Product: COC(=O)Cc1cscc1C(=O)O

Procedure:
Methyl (4-carboxy-3-thienyl)acetate was prepared from 4-bromothiophen-3-carboxylic acid and methyl acetoacetate by the method described by D. E. Ames and O. Ribeiro, J Chem.Soc., Perkin I, 1975, 1390, for the preparation of the corresponding ethyl ester. It is a solid which, after crystallisation from aqueous methanol, had mp 121°-122° C., 1H nmr: delta 3.72 (3H, s), 3.95 (2H, s), 7.18 (1H, d J 3 Hz), 8.27 (1H, d J 3 Hz) ppm.
Reaction SMILES: [NH:1]([CH2:3][CH2:4][OH:5])[NH2:2].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([C:18]3[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=3)[C:16](=[O:27])[C:15](=O)[CH:14]2[C:29](=O)[CH2:30][CH3:31])=[CH:9][CH:8]=1.CC(O)=O.S(=O)(=O)(O)N>CO>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[C:14]3[C:29]([CH2:30][CH3:31])=[N:2][N:1]([CH2:3][CH2:4][OH:5])[C:15]=3[C:16](=[O:27])[N:17]2[C:18]2[CH:23]=[C:22]([CH3:24])[C:21](=[O:25])[N:20]([CH3:26])[CH:19]=2)=[CH:9][CH:8]=1
Reactant: CCC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Reactant: NNCCO
Agent: NS(=O)(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: CCc1nn(CCO)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 90 °C
Yield: 45 %

Procedure:
To a solution of 2-hydrazinylethanol (76 mg, 1.0 mmol) in MeOH (2 mL) was added 5-(4-chlorophenyl)-1-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-4-propionylpyrrolidine-2,3-dione (Step 60.1) (204 mg, 0.5 mmol) and the reaction mixture was heated for 1 hr at 70° C. and for 0.5 hr at 90° C. in the MW. The volume of MeOH was reduced to 1 mL and AcOH (2 mL) and sulfamic acid (97 mg, 1.0 mmol) were added. The reaction mixture was heated for 1 h at 110° C. in the MW. The reaction mixture was concentrated under reduced pressure. The residue was basified with 20% K2CO3 solution and extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was first purified by silica gel column chromatography (hexane/EtOAc/MeOH 80:20:2 to 0:10:1) then further purified by preparative achiral SFC (column Propyl-pyridyl-urea, gradient 15-20% in 6 min_total 11 min) to afford the title product (97 mg, 0.225 mmol, 45% yield) as colorless foam. tR: 0.84 min (LC-MS 2); ESI-MS: 427 [M+H]+ (LC-MS 2); Rf=0.21 (EtOAc/MeOH 9:1); 1H NMR (400 MHz, CDCl3) δ ppm 0.91 (t, J=7.6 Hz, 3H) 2.01 (s, 3H) 2.25-2.48 (m, 2H) 3.37 (s, 3H) 3.44 (t, J=6.3 Hz, 1H) 3.95-4.05 (m, 2H) 4.43 (dd, J=5.6, 3.7 Hz, 2H) 5.50 (s, 1H) 6.91-7.03 (m, 4H) 7.25 (d, J=8.3 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11]N(C)C.[C-:15]#[N:16].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:15]#[N:16]
Reactant: CN(C)Cc1c[nH]c2ccc(Cl)cc12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c[nH]c2ccc(Cl)cc12
Temperature: 140 °C
Yield: 62.1 %

Procedure:
A solution of aqueous formaldehyde (37%, 2.95 mL, 66.0 mmol) and dimethylamine (40%, 5.30 mL, 66.0 mmol) in 20 mL EtOH was cooled to 0° C. 5-Chloroindole (4.0 g, 26.4 mmol) was dissolved in a HOAc:EtOH mixture (1:1, 40 mL) and added dropwise to the reaction mixture. After stirring at this temperature for 2 h, the mixture was allowed to warm to room temperature and stir overnight. The mixture was added to a sat'd solution of NaHCO3. 1 N NaOH was added until the pH was between 9-10. The resulting mixture was extracted with CH2Cl2 (3×). The organics were combined and washed with a sat'd aq. NaCl, dried over MgSO4, filtered and concentrated in vacuo to give 4.65 g (85%) of 5-chloro-3-[(dimethylamino)methyl]indole as a yellow powder. Without further purification, 5-chloro-3-[(dimethylamino)methyl]indole (4.65 g, 22.4 mmol) was dissolved in dimethylformamide (80 mL) at room temperature with stirring. To this was added KCN (2.18 g, 33.5 mmol) in H2O (10 mL). The mixture was warmed to 140° C. and stirred for 14 h. H2O was added and the mixture was extracted with EtOAc (2×). The organics were combined and washed with sat'd brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by SiO2 flash chromatography (3:2, Heptane: EtOAc) to give 2.65 g (63%) of 5-chloroindole-3-acetonitrile. 1H NMR (DMSO-d6, 300 MHz) δ11.30 (br s, 1H), 7.63 (s, 1H), 7.42-7.38 (m, 2H), 7.05 (d, J=6.0 Hz, 1H), 5.70 (s, 2H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[C:3]([C:5]1[NH:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1)=O.[C:15]([NH:18][NH2:19])([NH2:17])=[NH:16].[ClH:20].Cl>C(O)C>[ClH:20].[ClH:20].[CH3:1][CH:2]([CH3:14])[C:3](=[N:19][NH:18][C:15]([NH2:17])=[NH:16])[C:5]1[NH:13][C:8]2=[CH:9][N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=1
Reactant: CC(C)C(=O)c1cc2ccncc2[nH]1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: CC(C)C(=NNC(=N)N)c1cc2ccncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To a solution of 2-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1-propanone (Example 80) (100 mg, 0.53 mmol) in ethanol (5 mL) were added aminoguanidine hydrochloride (58 mg, 0.53 mmol) and 6 N HCl (0.2 mL). The reaction mixture was heated to reflux under N2. After 2 h, heating was terminated and the reaction mixture was cooled to room temperature. Purification by column chromatography (silica gel, 5 to 20% methanol in methylene chloride) produced [[2-methyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)propylidene]amino]guanidine dihydrochloride (28 mg, 26%) as a yellow solid: mp 242-245° C.; 1H NMR (500 MHz, CD3OD) δ 1.49 (6H, d, J=7.1 Hz), 3.50-3.54 (1H, m), 7.15 (1H, s), 7.72 (1H, d, J=5.5 Hz), 8.11 (1H, d, J=5.6 Hz), 8.77 (1H, s); ESI MS m/z 245 [C12H16N6+H]+; HPLC (Method A) >99% (AUC) tR=11.9 min.