Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[F:6][C:7]([F:24])([F:23])[C:8]([NH:10][CH2:11][C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=1)=[O:9]>C(O)C>[NH2:20][C:16]1[CH:15]=[C:14]([C:13]#[C:12][CH2:11][NH:10][C:8](=[O:9])[C:7]([F:6])([F:23])[F:24])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NCC#Cc1cccc([N+](=O)[O-])c1)C(F)(F)F
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc(C#CCNC(=O)C(F)(F)F)c1

Procedure:
Tin(II) chloride dihydrate was added (6.5 g, 28.67 mmol) to a solution of 2,2,2-trifluoro-N-(3-(3-nitrophenyl)prop-2-ynyl)acetamide (1.95 g, 7.16 mmol) in ethanol and the reaction mixture was stirred under reflux overnight. The mixture was concentrated under reduced pressure to give dark brown viscous liquid which was partitioned between saturated aqueous NaHCO3 and EtOAc. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give N(3-(3-aminophenyl)prop-2-ynyl)-2,2,2-trifluoroacetamide as brown oil. Yield (0.75 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 7.28 (s, 1H), 6.94 (t, J=7.8 Hz, 1H), 6.44-6.37 (m, 3H), 5.09 (bs, 2H), 3.99 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11]([OH:20])=[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]3=[N:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[C:23]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:20])[C:12]3[CH:18]=[C:17]([I:19])[S:16][C:13]=3[N:14]([CH3:23])[CH:15]=2)=[O:9])=[CH:21][CH:22]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2sc(I)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)sc21
Temperature: 90 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of N-(4-chlorobenzyl)-4-hydroxy-2-iodothieno-[2,3-b]pyridine-5-carboxamide (Example No. 2) (2.00 g) in DMF (14 mL) are added K2CO3 (1.76 g) and iodomethane (0.79 mL). The reaction is heated to 90° C. and stirred for 18 h. The reaction mixture is concentrated in vacuo. The resulting residue is partitioned between H2O (100 mL) and CH2Cl2 (200 mL). The aqueous layer is extracted with CH2Cl2 (3×150 mL). The combined organic layers are dried with MgSO4, filtered, and concentrated in vacuo. The resulting off-white solid is recrystallized from ethanol to yield 1.78 g (92%) of the title compound as an off-white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])N)=[CH:5][CH:4]=1.[CH3:20][CH2:21][O:22][C:23]([CH2:25][CH:26]1[C:31](=O)[CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:24]>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:26]([CH2:25][C:23]([O:22][CH2:21][CH3:20])=[O:24])[CH2:31][CH2:30][CH2:29][C:28]=3[C:15]3[C:10]2=[C:11]([Cl:17])[CH:12]=[C:13]([Cl:16])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(Cl)cc(Cl)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2,4-dichlorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][OH:14])[O:4]1.O[N:16]1C(=O)C2C(=CC=CC=2)C1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.O.NN>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([CH2:13][O:14][NH2:16])[O:4]1
Reactant: COC1O[C@H](CO)[C@H]2OC(C)(C)O[C@@H]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: COC1O[C@H](CON)[C@H]2OC(C)(C)O[C@@H]12
Yield: 50 %

Procedure:
The title compound was prepared using the procedure described for Example 2K by using ((3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (2.04 g, 10 mmol), CH2Cl2 (25 mL), 2-hydroxyisoindoline-1,3-dione (2.0 g, 12 mmol), triphenylphosphine (4.0 g, 15 mmol), diisopropylazodicarboxylate (3.0 ml, 15 mmol) and hydrazine hydrate (2.0 mL, 20 mmol) to afford 1.12 g of 04(3aR,4R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)hydroxylamine (2Y) (50%, over two steps) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (s, 3H) 1.26 (s, 3H) 3.31 (s, 3H) 3.59-3.75 (m, 2H) 4.44 (t, J=7.20 Hz, 1H) 4.56 (d, J=5.81 Hz, 1H) 4.67 (d, J=6.06 Hz, 1H) 4.92-5.00 (m, 1H). MS (ES) [M+H] calculated for C9H18NO5, 220.11; found 220.10.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:37])[CH:34]([CH3:36])[CH3:35]>N1C=CC=CC=1>[C:33]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([C:18](=[O:19])[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=3)=[C:9]([CH:30]([CH3:32])[CH3:31])[N:8]2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)(=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Oc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1
Yield: 7.6 %

Procedure:
Following General Procedure B, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 9 mg, 0.021 mol) in pyridine (1 ml) was reacted with isobutyryl chloride (4.1 μl, 0.21 mmol) to yield the title compound (8 mg, 80%).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13](=O)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>C(O)C>[CH2:1]([N:4]([CH2:12][C:13](=[N:21][OH:22])[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1cccs1)C(=O)OC(C)(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: C=CCN(CC(=NO)c1cccs1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl N-allyl-N-[2-oxo-2-(2-thienyl)ethyl]carbamate (15.2 g, 54.0 mmol), hydroxylamine hydrochloride (5.63 g, 81.0 mmol) and sodium acetate (6.65 g 81.0 mmol) in ethanol (216 mL) is stirred at 70° C. for 18 hours. The reaction is cooled and the solvent removed under reduced pressure. The residue is diluted water (100 mL) and extracted with dichloromethane. The organic layers are combined dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound as a mixture of E and Z isomers, which is used without further purification (16 g, >98%): ES/MS (m/e): 197 (M+H-100).
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[O:5].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[O:5]=[C:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH3:7]
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
tert-butyl 1-(N-methoxy-N-methylcarbamoyl)ethylcarbamate (39) (2.3 g, 10.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (100 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (30.0 mL, 30.0 mmol, 3.0 equiv.) was added over 8 min. The reaction stirred for 1.0 h at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (60 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (40 mL) and extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat. NaCl (1×50 mL), and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 3.1 g of crude material. The residue was purified by flash column chromatography (15% EtOAc/Hexanes) to give 2.2 g (86%) of 40 as a colorless oil.10 Rf=0.25 (15% EtOAc/Hexanes); IR (film) 3356, 2977, 1680, 1164 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=7.5 Hz, 2H, Ph-H), 7.59 (t, J=7.5 Hz, 1H, Ph-H), 7.48 (t, J=7.5 Hz, 2H, Ph-H), 5.62 (br d, J=6.5 Hz, 1H, carbamate-NH), 5.30 (t, 1H, Boc-NH—CH), 3.78 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.46 (s, 9H, Boc-t-butyl-CH3), 1.40 (d, J=7.0 Hz, 3H, CH—CH3); 13C NMR (125 MHz, CDCl3) δ 199.6, 155.5, 134.3, 133.9, 129.0, 128.8, 80.0, 51.3, 28.6, 20.1; LRMS (ESI-MS m/z): Mass calcd for C14H19NO3 [2M]+, 498.62. Found 499. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.[NH2:17][C:18]1[CH:23]=[C:22]([OH:24])[C:21]([CH3:25])=[CH:20][CH:19]=1>C(OCCO)C>[OH:24][C:22]1[CH:23]=[C:18]([NH:17][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)[CH:19]=[CH:20][C:21]=1[CH3:25]
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Cc1ccc(N)cc1O
Solvent: CCOCCO
Product: Cc1ccc(Nc2c(C#N)cnc3c2sc2ccccc23)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
A mixture of 300 mg (1.20 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile and 160 mg (1.32 mmol) of 5-amino-o-cresol in 5 mL of 2-ethoxyethanol is heated at reflux temperature for 8 hours, then stirred at room temperature overnight. The reaction mixture is partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to provide 220 mg (55%) of a light yellow solid, mp 260° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]([NH:29][S:30]([C:33]1[S:34][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:36][CH:37]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[S:34][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:9]=[C:10]([CH3:24])[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=4)[N:13]=3)[CH:3]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1

Procedure:
N-tert-Butyl-5-{3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyrimidine (example E.47) (0.39 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.41 g, 1.2 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.16 g), which was subsequently deprotected.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:10]([CH2:11][CH3:12])=[N:9][C:8]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:7]=2[C:6]=1[NH:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.[CH2:34]([O:36][C:37]1[C:38](=O)[C:39](=[O:44])[C:40]=1[O:41]CC)[CH3:35]>C(O)C>[CH2:16]([N:13]1[C:8]2=[N:9][C:10]([CH2:11][CH3:12])=[C:5]([CH2:4][NH:3][C:38]3[C:39](=[O:44])[C:40](=[O:41])[C:37]=3[O:36][CH2:34][CH3:35])[C:6]([NH:18][CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[C:7]2[CH:15]=[N:14]1)[CH3:17]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1c(NCc2c(CC)nc3c(cnn3CC)c2NC2CCOCC2)c(=O)c1=O
Reaction time: 8 h

Procedure:
A suspension of 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine dihydrochloride (0.60 g, 1.6 mmol) in ethanol (8 mL) was treated with N,N-diisopropylethylamine (DIEA, 0.57 mL, 3.3 mmol), giving a clear, homogeneous mixture, which was then cooled in an ice-water bath. 3,4-Diethoxycyclobut-3-ene-1,2-dione (TCI America, 0.41 g, 0.36 mmol) was then added dropwise via syringe. Following completion of the addition, the mixture was allowed to regain room temperature and stir overnight. The precipitated solid was collected by Büchner filtration, washed with ethanol, and dried under house vacuum to provide the title compound as a white solid. ES/MS calcd. for C22H30N5O4+ 428.2. found m/z=428.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3].Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:11]=2)[S:7][C:6]=1[C:17]([NH2:19])=[O:18])=[O:3]
Reactant: NC(=O)Nc1cc(-c2cccc(O)c2)sc1C(N)=O
Reactant: ClCCN1CCCCC1
Product: NC(=O)Nc1cc(-c2cccc(OCCN3CCCCC3)c2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 6 and N-(2-chloroethyl)piperidine.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[C:8]([CH3:28])=[CH:7][C:5]=2[N:6]=1.[CH3:29][N:30]1[C:38]2[CH:37]=[N:36][C:35]([Sn](CCCC)(CCCC)CCCC)=[N:34][C:33]=2[C:32]([CH3:52])=[N:31]1>O1CCOCC1.[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>[C:24]([O:23][C@@H:18]([C:9]1[C:8]([CH3:28])=[CH:7][C:5]2[N:6]=[C:2]([C:35]3[N:36]=[CH:37][C:38]4[N:30]([CH3:29])[N:31]=[C:32]([CH3:52])[C:33]=4[N:34]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH3:22])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc2c(n1)c(C)nn2C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ncc4c(n3)c(C)nn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
A mixture of (S)-methyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (0.055 g, 0.107 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-pyrazolo[4,3-d]pyrimidine (0.058 mg, 0.133 mmol), copper(I) iodide (6 mg, 0.032 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.012 mmol) in dioxane (1 mL) was heated at 90° C. for 16 hr. Reaction mixture was cooled to rt, filtered through a syringe filter and purified by CombiFlash (0 to 70% EtOAc/Hex) to give title product. LCMS-ESI+: calc'd for C28H29ClN5O3S: 550.2 (M+H+); Found: 550.3 (M+H+); 1H NMR (400 MHz, Methanol-d4) δ 9.32 (s, 1H), 7.88 (s, 1H), 7.70-7.53 (m, 4H), 5.30 (s, 1H), 4.13 (s, 3H), 3.75 (s, 3H), 2.57 (s, 3H), 2.54 (s, 3H), 0.97 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9](S(C)(=O)=O)=[N:10][CH:11]=2)[CH2:3][CH2:2]1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([C:16]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[C:19](=[O:26])[N:18]([CH3:27])[CH:17]=3)=[N:8][C:9]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[N:10][CH:11]=2)[CH2:3][CH2:2]1
Reactant: Cn1cc(-c2nc(S(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2
Reactant: CS(N)(=O)=O
Product: Cn1cc(-c2nc(NS(C)(=O)=O)ncc2OCC2CC2)c2c(c1=O)CCCC2

Procedure:
The title compound of step 4 was treated with MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz): δ 8.18 (s, 1H), 7.38 (s, 1H), 3.74 (d, J=6.4 Hz, 2H), 3.51 (s, 3H), 3.28 (s, 3H), 2.60-2.53 (m, 2H), 2.50-2.46 (m, 2H), 1.74-1.71 (m, 2H), 1.64-1.59 (m, 2H), 1.13-1.10 (m, 1H), 0.60-0.58 (m, 2H), 0.25-0.24 (m, 2H). LCMS: 405.1 (M+H)+
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH2:20][CH3:21])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])[CH2:19][CH2:20][CH3:21])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: CCC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCCC[C@@H](O)[C@H](CCC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 11 (123 mg, 0.44 mmol) and 1-bromopentadecane (318 mg, 1.09 mmol), alcohol 65 was obtained as a colorless oil (161 mg, 75% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](N)=[N:9][NH:10][C:3]=12.N([O-])=O.[Na+]>O.CC(O)=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[N:9][NH:10][C:3]=12
Reactant: Nc1n[nH]c2c(I)ccnc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Ic1ccnc2cn[nH]c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
To a suspension of 7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (23 g) in water (90 mL) and AcOH (75 mL) was added dropwise a solution of sodium nitrite (12.6 g) in water (90 mL) over 30 minutes at 0° C. The mixture was warmed to room temperature and stirred for 24 hours. Then the mixture was cooled to 0° C. again and stirred for another 0.5 hour to give a solid which was collected by filtration and washed with cold water. The solid was suspended in aqueous HI (20 mL 50% HI diluted to 300 mL with water) and dimethoxymethane (600 mL). This mixture was heated to 80° C. for 3 hours, then cooled to room temperature, neutralized with Na2CO3 solution, and then extracted with ethyl acetate. The organic layer was collected, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to give a residue. This residue was purified by column chromatography eluting with 1:2 petroleum ether:ethyl acetate to afford the title compound as a light yellow solid (7.8 g). 1H-NMR (400 MHz, DMSO-d6) 7.86 (d, J=4.4 Hz, 1H) 8.16 (d, J=4.4 Hz, 1H) 8.46 (s, 1H) 13.67 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:26])[C:11]3[C:16]([O:17][C:18]=2[C:19]=1[O:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23])=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:3]#[CH:4]>CO.[Pd]>[CH3:1][C:2]([CH3:27])([O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[O:26])[C:11]3[C:16]([O:17][C:18]=2[C:19]=1[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH2:23])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=[CH2:4]
Reactant: C#CC(C)(C)Oc1ccc2c(=O)c3ccccc3oc2c1OC(C)(C)C#C
Agent: [Pd]
Solvent: CO
Product: C=CC(C)(C)Oc1ccc2c(=O)c3ccccc3oc2c1OC(C)(C)C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
To a solution of 3,4-bis-(1,1-dimethyl-prop-2-ynyloxy)-xanthen-9-one (318 mg, 0.882 mmol) in methanol (25 mL) was added Lindlar's catalsyt (Pd, 5 wt % on calcium carbonate, 75 mg) under hydrogen (1 atm). The mixture was stirred at room temperature for 1 h, then the mixture was filtered through a syringe filter and the solvent was evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexanes/10-25%) to give the product as a white solid (249 mg, 77%): 1H NMR (CDCl3,300 MHz) δ 8.31 (dd, J=1.8, 8.1 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.70 (m, 1H), 7.50 (dd, J=0.9, 8.7 Hz, 1H), 7.37 (m, 1H), 7.13 (d, J=9.0 Hz, 1H), 6.30 (dd, J=10.8, 17.7 Hz, 1H), 6.20 (dd, J=11.1, 17.1 Hz, 1H), 5.25-5.16 (m, 3H), 5.03 (dd, J=0.9, 10.5 Hz, 1H), 1.59 (s, 3H), 1.58 (s, 3H).
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].[CH3:22][NH:23][C:24](=[O:27])[NH:25][NH2:26].Cl.C(=O)(O)[O-].[Na+]>O.C(O)C>[CH3:22][NH:23][C:24](=[O:27])[NH:25]/[N:26]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:19]([CH3:21])[CH3:20])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=2
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCN(C(C)C)C(C)C
Reactant: CNC(=O)NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CNC(=O)N/N=C1/C(=O)N(CCN(C(C)C)C(C)C)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.8 %

Procedure:
To a solution of 1.00 g of 1-(2-diisopropylaminoethyl)-5-methylisatin and 0.34 g of 4-methylsemicarbazide in 15 ml of a mixture of ethanol and water (2:1) was added 3.8 ml of a 1N-hydrochloric acid. The mixture was stirred for 16 hours at room temperature. To the reaction mixture was added an aqueous sodium bicarbonate solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 0.77 g of (E)-1-(2-diisopropylaminoethyl)-5-methylisatin 3-(4-methylsemicarbazone) having a melting point of 157.5°-158.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]4([CH2:16][CH2:15]4)[C:5]=3[C:4]=2[CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([C:19]([F:29])([F:18])[F:28])=[CH:25][CH:24]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:17])[C:14]4([CH2:16][CH2:15]4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C12CC2
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2ccc(C(F)(F)F)nc2)C12CC2

Procedure:
The title compound is prepared from a mixture of 8′-chloro-2′-methyl-2′,3′,4′,5′-tetrahydrospiro[cyclopropane-1,1′-pyrido[4,3-b]indole], 2-(trifluoromethyl)-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:15]3[C:10]([C:11]([NH2:16])=[N:12][CH:13]=[N:14]3)=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:21]=4)[CH:8]=2)[CH2:3][CH2:2]1.[Cl-].ClC[C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[NH2:16][C:11]1[C:10]2=[C:9]([C:17]3[CH:18]=[CH:19][C:20]4[C:24]([CH:25]=3)=[N:23][N:22]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:21]=4)[CH:8]=[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:6][CH2:5]3)[N:15]2[N:14]=[CH:13][N:12]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(Cc5cccnc5)nc4c3)c12
Agent: [Cl-]
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5cccnc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 65 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 7-piperidin-4-yl-5-[2-(pyridin-3-ylmethyl)-2H-indazol-6-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting dimethylcarbamyll chloride for 2-chloro-N,N-dimethylacetamide as starting material, 50 mg (65%) of the desired product was isolated. 1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1 H) 8.49 (d, 1 H) 8.43 (s, 1 H) 7.75-7.80 (m, 3 H) 7.63 (s, 1 H) 7.42 (dd, 1 H) 7.21 (d, 1 H) 6.56 (s, 1 H) 5.71 (s, 2 H) 3.76 (d, 2 H) 3.34 (m, 1 H) 2.94 (dd, 2 H) 2.84 (s, 6 H) 2.06 (dd, 2 H) 1.73 (dt, 2 H). LC-MS [M+H]+=496.4, RT=1.08 min.