Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C@H:2]2[CH2:21][N:6]3[C:7]4[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]3[CH2:4][CH2:3]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NS(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
To a CH2Cl2 solution (0.2 M) of propyl ([7R]-7-amino-6,7,8,9-tetrahydro-pyrido[1,2-α]indo1-10-yl)acetate from Step 6 was added 4-fluorobenzenesulfonyl chloride (1.1 equiv.) followed by triethylamine (3 equiv.) and DMAP (1 equiv.). The reaction mixture was stirred for 12 h at rt. The mixture was concentrated under reduced pressure, diluted with EtOAc, and washed with aqueous NaHCO3, water and finally with brine. The organic layer was dried with Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel using a CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (10:90 to 50:50) to give the title compound (97%) as a colorless foam.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:16]([C:18]3[C:19]([O:31][CH3:32])=[C:20]([CH:27]4[CH2:30][NH:29][CH2:28]4)[C:21]([CH3:26])=[C:22]([CH:25]=3)[C:23]#[N:24])[CH3:17])[N:11]=[C:12]([CH:13]([F:15])[F:14])[C:5]=12.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:29]1[CH2:30][CH:27]([C:20]2[C:21]([CH3:26])=[C:22]([CH:25]=[C:18]([CH:16]([N:10]3[C:6]4=[N:7][CH:8]=[N:9][C:4]([NH2:3])=[C:5]4[C:12]([CH:13]([F:14])[F:15])=[N:11]3)[CH3:17])[C:19]=2[O:31][CH3:32])[C:23]#[N:24])[CH2:28]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CNC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C(C)n2nc(C(F)F)c3c(N)ncnc32)cc(C#N)c(C)c1C1CN(C(C)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-{1-[4-amino-3-(difluoromethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-3-azetidin-3-yl-4-methoxy-2-methylbenzonitrile dihydrochloride (21 mg, 0.043 mmol, racemic intermediate from Example 129, Step 2), acetyl chloride (3.4 μL, 0.048 mmol), and triethylamine (18 μL, 0.13 mmol) in methylene chloride (0.3 mL) was stirred overnight at room temperature. The solvents were evaporated and the crude material was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C22H24F2N7O2 (M+H)+: m/z=456.2; Found: 456.2.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16](=O)[NH:17][N:18]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:16]1[N:17]=[N:18][C:13]([CH2:12][CH2:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCC[C@H]1CC[C@H](CCc2ccc(=O)[nH]n2)CC1
Product: CCCC[C@H]1CC[C@H](CCc2ccc(Cl)nn2)CC1
Temperature: 0 °C

Procedure:
21.0 g of 6-[2-(trans-4-butylcyclohexyl)ethyl]-3(2H)-pyridazinone are treated with 20 ml of phosphorus oxychloride and slowly heated to reflux. After boiling under reflux for 20 minutes, the excess phosphorus oxychloride is distilled off. The residue is cooled 0° C., hydrolyzed cautiously with 100 g of crushed ice, then neutralized with sodium hydrogen carbonate and extracted three times with 100 ml of tert.butyl methyl ether each time. The combined organic phases are dried over sodium sulphate and freed from solvent on a rotary evaporator. The crude product of 3-chloro-6-[2-(trans-4-butylcyclohexyl)ethyl]pyridazine obtained is recrystallized from ethanol.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:32][NH:33][CH3:34]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:33]([CH3:34])[CH3:32])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CNC
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN(C)C)cc1)c1ccc2oc(Cl)cc2c1
Yield: 38 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (70 mg, 1.0 eq, made by example 11, step D) was reacted with dimethylamine (1 mL) in MeOH (8 mL) under reflux to give the desired product (27 mg, 38%, Z/E=1/1.2) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 & 7.21 (s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.08 & 7.06 (d, J=9.2 Hz, 2H), 7.00 & 6.97 (d, J=8.4 Hz, 1H), 6.79 & 6.67 (d, J=8.6 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 6.45 & 6.24 (d, J=8.8 Hz, 2H), 6.43 & 6.41 (s, 1H), 4.10 & 3.89 (t, J=5.2 Hz, 2H), 2.86 & 2.75 (t, J=5.2 Hz, 2H), 2.49 (q, J=7.2 Hz, 2H), 2.44 & 2.37 (s, 6H), 0.91 (t, J=7.2 Hz, 3H); m/z=462[M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2].[CH2:24](Br)[C:25]#[CH:26].C1CCN2C(=NCCC2)CC1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH2:26][C:25]#[CH:24])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:22])=[CH:18][C:17]=1[F:23])=[O:5])[CH3:2]
Reactant: C#CCBr
Reactant: CCOC(=O)c1[nH]c2ccncc2c1Nc1ccc(I)cc1F
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C#CCn1c(C(=O)OCC)c(Nc2ccc(I)cc2F)c2cnccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
A mixture of 3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (70.0 mg, 0.164 mmol), propargyl bromide (80% in xylene, 45.5 μL, 0.41 mmol, 2.5 eq), DBU (3.2 mL), and anhydrous THF (3.2 mL) was stirred at 50° C. under N2 for 1 h, and then at ambient temperature for 17 h. The solvent was evaporated and the resultant residue was diluted with ethyl acetate (75 mL). The organic layer was washed with water (20 mL), followed by brine (20 mL), dried (Na2SO4), filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography (silica, ISCO, 45 mL/min, Hexane:EtOAc, gradient 100:1 to 1:100). Crystallization from EtOAc-hexane gave the desired compound as a yellow solid (34.5 mg, 45.3%). 1H NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1H), 8.44 (d, J=5.87 Hz, 1H), 7.60 (s, 1H), 7.45 (dd, J=10.26 Hz, 2.0 Hz, 1H), 7.37-7.27 (m, 2H), 6.87 (t, J=9.20 Hz, 1H), 5.29 (s, 2H), 4.46 (q, J=7.14 Hz, 2H), 2.29 (t, J=2.47 Hz, 1H), 1.49-1.40 (t, J=7.20 Hz, 3H); LC-MS (method D): [M+H]+=464.0, RT=2.40 min.
Reaction SMILES: C[C@H:2]1[CH2:30][O:29][C@@:5]2(O[C@H:8]3[CH2:10][C@H:11]4[C@@H]5CC=C6C[C@@H](O)CC[C@]6(C)[C@H]5CC[C@:12]4(C)[C@H:7]3[C@@H:6]2C)[CH2:4][CH2:3]1.[OH-].[K+].C(OCC(CC)CCCC)C1[O:36]C1>C1(C)C=CC=CC=1>[CH2:6]([CH:5]([O:29][CH2:30][CH3:2])[CH:4]1[O:36][CH2:3]1)[CH2:7][CH2:8][CH2:10][CH2:11][CH3:12]
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Reactant: CCCCC(CC)COCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCCCCC(OCC)C1CO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a 250 mL, round bottom 3-neck flask equipped with a condenser, a nitrogen in/out let, a mechanical stirrer, a thermo-watch, and a heating mantle, a mixture of 30 g of 35,000 Mw PEG and toluene (80 mL) was heated to 60° C. At this temperature, KOH (0.77 g, 0.02 mol, in 1 g of water) was added and the reaction mixture was stirred for 1 hour. 2-Ethyl hexyl glycidyl ether (1.91 g, 0.02 mole) was added and the reaction temperature was kept at 110° C. for 5 hours. After the reaction mass was cooled to 60° C., toluene (80 mL) was further added. The solution was precipitated into 300 mL of hexane. After filtration and washing with ethyl acetate (100 mL×3×) and drying in vacuum, a white polymer (31 g) was obtained. 1H NMR showed 5.2% hydrophobe incorporation. The Brookfield viscosity of a 5% aqueous solution of this oligomer was >200,000 cps (BF LV, S-63, 0.3 rpm at 25° C.). Paint performance: SG10 M (standard formulation). TE %=0.11, Viscosity Loss upon Tinting (VLT)=−24 KU. For UCAR 379 G, TE %=0.28, VLT=−30 KU.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1.[CH:35]([S:37]([CH:40]=C)(=[O:39])=[O:38])=[CH2:36].Cl.C(OCC)C>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[C:14]([N:15]2[N:24]=[C:23]3[C:17]([CH2:18][CH2:19][O:20][C:21]4[CH:28]=[CH:27][C:26]([CH:29]5[CH2:34][CH2:33][N:32]([CH2:36][CH2:35][S:37]([CH3:40])(=[O:39])=[O:38])[CH2:31][CH2:30]5)=[CH:25][C:22]=43)=[CH:16]2)=[N:13][CH:12]=[N:11]1
Reactant: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2cc(C4CCNCC4)ccc2OCC3)c(F)c1
Reactant: C=CS(=O)(=O)C=C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)CCN1CCC(c2ccc3c(c2)-c2nn(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)CC1

Procedure:
Following the procedure for 152, 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-piperidin-4-yl-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with vinyl sulfone. The crude product was dissolved in DCM and treated with 4N HCl. After stirring for 10 min diethyl ether was added and the solid precipitate collected by filtration to give 175 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 10.63 (s, 1H); 8.45 (s, 1H); 8.30 (s, 1H); 7.85 (td, J=8.75, 5.90 Hz, 1H); 7.72 (t, J=9.62 Hz, 1H); 7.42 (t, J=8.57 Hz, 1H); 7.22 (d, J=2.33 Hz, 1H); 7.11 (dd, J=8.45, 2.37 Hz, 1H); 6.97 (d, J=8.34 Hz, 1H); 4.22 (t, J=5.02 Hz, 2H); 3.82 (t, J=7.50 Hz, 2H); 3.76-3.63 (m, 2H); 3.59 (d, J=9.30 Hz, 2H); 3.16 (s, 3H); 3.14 (m, 2H); 3.06 (t, J=5.04 Hz, 2H); 2.66 (s, 1H); 1.96-1.76 (m, 4H). LCMS: RT=7.54 min, M+H+=555
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[NH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:25]3[N:11]4[C:12]5[CH:24]=[CH:23][CH:22]=[N:21][C:13]=5[NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:10]4=[N:9][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:31][CH:30]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(-c3c(-c4ccc(O)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 34 h
Yield: 116.6 %

Procedure:
tert-Butyl (1-{4-[2-(4-hydroxyphenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (34 mg, 0.060 mmol) in MeOH (0.5 mL) was added 4N HCl-dioxane (2 mL) and stirred at room temperature for 34 hours. The mixture was concentrated to afford the desired product (33 mg, 96%) as a brown solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.71-8.67 (m, 3H), 8.13 (dd, J=4.6, 1.4 Hz, 1H), 7.94 (dd, J=8.0, 1.4 Hz, 1H), 7.53 (d, J=9.7 Hz, 2H), 7.41 (t, J=7.7 Hz, 1H), 7.32-7.28 (m, 4H), 7.15 (t, J=7.4 Hz, 1H), 6.89 (dd, J=8.6, 1.7 Hz, 1H), 6.76 (dd, J=8.6, 4.6 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H), 3.73-3.65 (m, 1H), 3.51-3.45 (m, 1H), 2.60-2.53 (m, 2H), 2.23-2.14 (m, 1H), 1.86-1.78 (m, 1H). LCMS: 472 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Cl)=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2].CC(C)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:26]=[N+:27]=[N-:28])=[N:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Cl)nc1-c1ccc(C(F)(F)F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1sc(N=[N+]=[N-])nc1-c1ccc(C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
To a stirred solution of 2.41 g (7.18 mmole) of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester, 2.4 mL of acetone and 2.4 mL of water was added 2.34 g (35.63 mmole) of sodium azide. The reaction mixture was heated at 70 degrees for 16 hours and then partitioned between 200 mL of ethyl acetate and 75 mL of water. The aqueous layer was extracted twice with 55 mL of ethyl acetate. The combined ethyl acetate layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2.44 g of 2-azido-4-(4-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid ethyl ester as a dark amber oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:15]3[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]4[CH:20]=[CH:19][S:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1.C(N(CC)CC)C>>[CH3:24][N:25]1[CH:29]=[C:28]([S:30]([N:1]2[CH2:6][CH2:5][CH:4]([C:7]3[C:15]4[C:10](=[C:11]([C:21]([NH2:23])=[O:22])[CH:12]=[C:13]([C:16]5[CH:20]=[CH:19][S:18][CH:17]=5)[CH:14]=4)[NH:9][CH:8]=3)[CH2:3][CH2:2]2)(=[O:32])=[O:31])[N:27]=[CH:26]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccsc5)cc34)CC2)c1

Procedure:
Following the general procedure in example 267, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indole-7-carboxamide (40 mg, 0.12 mmol), 1-methyl-1H-imidazole-4-sulfonyl chloride (29.7 mg, 0.18 mmol) and triethylamine (0.05 mL, 0.36 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (20 mg, 34%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@H:13]2[CH2:15][C@@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O1CCCC1>[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@H:13]2[CH2:15][C@@H:14]2[CH2:16][NH:17][C:25](=[O:27])[CH3:26])=[N:5]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c([C@H]3C[C@@H]3CN)cccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1C[C@@H]1c1cccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a solution of 1-[(1S,2S)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (300 mg, 1.09 mmol) and triethylamine (305 μL, 2.19 mmol) in tetrahydrofuran (10 mL) was added acetic anhydride (124 μL, 1.31 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=5/95→20/80) to give the title compound (242 mg, yield 99%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]5)[C:19]([CH:36]=[CH2:37])=[CH:18][CH:17]=4)=[N:14][N:13](COCC[Si](C)(C)C)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.FC(F)(F)S(O)(=O)=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([C:16]4[N:21]=[C:20]([N:22]5[CH2:27][CH2:26][CH2:25][C@H:24]([NH2:28])[CH2:23]5)[C:19]([CH:36]=[CH2:37])=[CH:18][CH:17]=4)=[N:14][NH:13][C:10]3=[CH:11][N:12]=2)[CH:2]=1
Reactant: C=Cc1ccc(-c2nn(COCC[Si](C)(C)C)c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=Cc1ccc(-c2n[nH]c3cnc(-c4cccnc4)cc23)nc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
The above (S)-tert-butyl 1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)-3-vinylpyridin-2-yl)piperidin-3-ylcarbamate (23.7 mg, 0.038 mmol) was dissolved in Trifluoroacetic Acid (2 mL) and Methylene chloride (2 mL). To the solution was add Trifluoromethanesulfonic acid (50 uL, 0.6 mmol) and Triethylsilane (30 uL, 0.19 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 307 as an off-white solid (5.1 mg, 34%). 1H NMR (400 MHz, DMSO) δ 9.32 (d, J=1.9 Hz, 1H), 9.20 (s, 1H), 9.11 (s, 1H), 8.59 (d, J=3.8 Hz, 1H), 8.46 (d, J=8.0 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H), 7.52 (dd, J=8.0, 4.7 Hz, 1H), 6.80 (dd, J=17.7, 11.0 Hz, 1H), 5.88 (d, J=17.6 Hz, 1H), 5.38 (d, J=11.3 Hz, 1H), 3.77 (d, J=9.7 Hz, 1H), 3.58 (d, J=12.1 Hz, 1H), 2.92-2.82 (m, 2H), 2.82-2.72 (m, 1H), 1.95 (d, J=12.7 Hz, 1H), 1.87-1.71 (m, 2H), 1.25 (dd, J=19.0, 10.7 Hz, 1H); ESI MS m/z=398.2 (M+1)
Reaction SMILES: [CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6]Cl)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1.[I-].[Na+].[NH:23]1[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[CH2:1]1[CH2:9][O:8][CH:4]([CH2:5][CH2:6][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH:3]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)[O:2]1
Reactant: O=C1CCc2cc(C3OCCOC3CCCl)ccc2N1
Reactant: c1nc[nH]n1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C3OCCOC3CCn3cncn3)ccc2N1
Temperature: 80 °C

Procedure:
10.5 Grams (35.5 mM) of 6-(1-ethylenedioxy-4-chlorobutyl)-3,4-dihydrocarbostyril was dissolved in 10.6 g (71 mM) of dimethylformamide, to this solution was added 10.6 g (71 mM) of sodium iodide, 5.4 g (78.1 mM) of 1H-1,2,4-triazol and 6.5 ml (46.2 mM) of DBU, and the whole mixture was heated at 80° C. for 7 hours with stirring. The reaction mixture was concentrated by removing the solvent by evaporation under reduced pressure, the residue was extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous magnesium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=40:1), and recrystallized from ethanol-n-hexane to yield 8.0 g of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl]-3,4-dihydrocarbostyril. Next, to a solution of 1 g (3.0 mM) of 6-[1-ethylenedioxy-4-(1H-1,2,4-triazol-1-yl)butyl] -3,4-dihydrocarbostyril with 10 ml of DMF was added 3 ml of 5%-hydrochloric acid and stirred for 2 hours at room temperature. After concentration by removal of the solvent, the residue was extracted with chloroform: methanol=3:1. The extract was washed with water, dried with an anhydrous magnesium sulfate, then concentrated by removal of the solvent. The resulting residue was recrystallized from chloroform-ethanol to yield 6-[4-(1H-1,2,4-triazol-1-yl)butyryl]-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:28][CH2:29][C:30]#[CH:31])(=O)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][C:29]#[CH:28])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
2.38 g (10.00 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 1.63 g (5.00 mmol) Cs2CO3 were heated in 25 ml acetonitrile at reflux for 5 min. 2.34 (10.0 mmol) 3-Butynyl tosylate was added and heating was continued for 2.5 h. Then 1.63 g (5.00 mmol) Cs2CO3 and 2.34 (10.0 mmol) of 3-butynyl tosylate were added and the mixture was stirred at 60° C. (2.5 h). The temperature was raised to 95° C. and stirring continued for 12 h. Every 3 h 1.63 g (5.0 mmol) Cs2CO3 and 2.34 g (10.0 mmol) of 3-butynyl tosylate were added. The solvent was evaporated and the residue was redissolved in dichloromethane, dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (SiO2, n-heptane/EtOAc 2.5%) yielded 0.67 g of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8](B(O)O)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].Br[C:21]1[CH:22]=[C:23]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:28][NH:27][C:24]2=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(P([Pd-2](Cl)(Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:21]2[CH:22]=[C:23]3[C:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH3:37])=[CH:28][NH:27][C:24]3=[N:25][CH:26]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: COCCOc1ccc(B(O)O)cc1OCCOC
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COCCOc1ccc(-c2cnc3[nH]cc(-c4ccccc4OC)c3c2)cc1OCCOC
Yield: 63.5 %

Procedure:
A vial is charged with 81.0 mg (0.300 mmol) of 3,4-bis(2-methoxyethoxy)phenylboronic acid, 60.6 mg (0.200 mmol) of 5-bromo-3-(2-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine and 8.3 mg (5 mol %) of bis(triphenylphosphino)palladium(II)-dichloride. 1.5 ml of acetonitrile and 1.5 ml of a 2 M aqueous solution of sodium carbonate were added and the mixture irradiated in a Personal Chemistry® microwave reactor to 150° C. for 15 minutes. The mixture was extracted with three times with 15 ml of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The dark brown residue (187 mg) was purified by flash chromatography on silicon using a gradient of ethyl acetate in hexane to give 57 mg of 5-[3,4-bis-(2-methoxy-ethoxy)-phenyl]-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as a colorless powder. 1H-NMR (d4-methanol) δ: 8.41 [1H] d (2.0 Hz), 8.17 [1H] d (2.0 Hz), 7.63 [1H] s, 7.56 [1H] dd (1.5 Hz, 7.5 Hz), 7.30 [1H] m; 7.26 [1H] d (2.5 Hz), 7.20 [1H] dd (2.3 Hz, 8.3 Hz), 7.11 [1H] d (8 Hz), 7.08 [1H] d (8.5 Hz), 7.05 [1H] dt (1 Hz, 7.5 Hz) 4.24 [2H] m, 4.19 [2H] m, 3.77 [4H] m, 3.44 [3H] s, 3.43 [3H] s. MS m/z: 449.2 [MH+], 471.1.1 [MNa+].
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]([N:57]1[CH:61]=[C:60]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)[CH:59]=[N:58]1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C>[CH2:50]([N:57]1[CH:61]=[C:60]([C:62]2[CH:63]=[C:64]([NH:68][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:65]=[CH:66][CH:67]=2)[CH:59]=[N:58]1)[C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cnn(Cc3ccccc3)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cnn(Cc5ccccc5)c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 61.3 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1-benzyl-1H-pyrazol-4-yl)-phenylamine (0.016 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 62% yield: LCMS (ESI) m/z 452 (MH+).