Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2.[N:33]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.Cl.CN(C)CCCN=C=NCC>ClCCl.[Cl-].[Na+].O>[S:1]1[C:5]([C:6]2[C:7]([O:27][CH3:28])=[CH:8][C:9]([O:25][CH3:26])=[C:10](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH:41][CH2:40][CH2:39][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:11]=2)=[CH:4][C:3]2[CH:29]=[CH:30][CH:31]=[CH:32][C:2]1=2
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
To a solution of 4-[3E-(5-Benzo[b]thien-2-yl-2,4-dimethoxyphenyl)-acryloyl]-benzoic acid (Ex-3, 0.44 mg, 1 mmol) and 2-morpholin-4-yl-ethylamine (0.18 mL) in dichloromethane (20 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2 mmol) and the mixture was stirred at room temperature for four hours. It was poured into brine (100 mL) and extracted with dichloromethane (2×50 mL). The organic phase was dried and evaporated. Chromatography (dichloromethane/methanol 50:1) gave the title compound as a yellow solid (0.43 g, 77%). 1H-NMR (300 MHz, CDCl3) δ 8.12 (d, J=16 Hz, 1H), 8.09 (d, J=8 Hz, 2H), 7.95 (s, 1H), 7.90 (d, J=8 Hz, 2H), 7.77–7.85 (m, 2H), 7.68 (s, 1H), 7.56 (d, J=16 Hz, 1H), 7.29–7.40 (m, 2H), 6.80–6.85 (br s, 1H), 6.58 (s, 1H), 4.04 (s, 3H), 4.01 (s, 3H), 3.75 (t, J=5 Hz, 4H), 3.59 (quad, J=5 Hz, 2H), 2.64 (t, J=5 Hz, 2H), 2.53 (t, J=5 Hz, 4H). Anal. calc. for C32H32N2O5S.H2O: C, 67.94; H, 5.88; N, 4.95; found: C, 68.12; H, 5.92; N, 4.96.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=4[Cl:24])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Reactant: O=C(Cl)c1ccccc1Cl
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4Cl)c3)csc12

Procedure:
3-[3-(2-Chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and 2-chlorobenzoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][NH:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[S:30][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(=O)NNC(=O)CNC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nnc(CNC(=O)OC(C)(C)C)s1
Yield: 261.8 %

Procedure:
To the solution of ethyl 2-(2-(2-(tert-butoxycarbonylamino)acetyl) hydrazinyl)-2-oxoacetate (9-4) (228 mg, 0.6913 mmol) in THF (10 mL) was added lawesson's reagent (354 mg, 0.8669 mmol). The solution was heated to reflux for 3 h. Then solvent was evaporated under reduced pressure and the residue was purified by chromatography on silica gel with the eluant (PE/EA/NEt3=10/1/1%; 5/1/1%; 2/1/1%). The yellow solid was obtained as the product (520 mg, 69%). 1H NMR (500 MHz, CDCl3) δ 5.31 (br, 1H), 4.76 (d, J=6.1 Hz, 2H), 4.51 (d, J=14, 7.1 Hz, 2H), 1.60-1.39 (m, 12H); LRMS (ESI) calculated M+H for C11H18N3O4S: 288.3; Found: 288.1.
Reaction SMILES: Cl.OC(CO)[CH2:4][NH:5][C:6]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:8]([C:9]([NH:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[O:10])[CH:7]=1.[Cl:26]C1C2C(=CC=CC=2)N=[C:29]([C:30](NC2NN=NN=2)=[O:31])C=1.NCC(O)CO>>[ClH:26].[OH:31][CH2:30][CH2:29][N:5]([CH3:4])[C:6]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:8]([C:9]([NH:11][C:12]2[NH:16][N:15]=[N:14][N:13]=2)=[O:10])[CH:7]=1
Reactant: O=C(Nc1nnn[nH]1)c1cc(NCC(O)CO)c2ccccc2n1
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Agent: Cl
Agent: NCC(O)CO
Product: CN(CCO)c1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
In a similar way, 4(2,3-Dihydroxypropylamino)-N(1H-tetrazol-5-yl)quinaldamide, hydrochloride, m.p. 264° (d) was prepared from 4-chloro-N (1H-tetrazol-5-yl)quinaldamide (Example 2) and 3-amino-1,2-propanediol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:9]1[O:10][C:11]3([CH2:17][S:18][C:8]=1[C:7](=[O:22])[C:6]2=[O:23])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:14]2[CH2:15][CH2:16][C:11]3([O:10][C:9]4[C:19]5[C:5]([C:6](=[O:23])[C:7](=[O:22])[C:8]=4[S:18][CH2:17]3)=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=5)[CH2:12][CH2:13]2)=[CH:27][CH:28]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCNCC2)CS1
Product: COc1ccc2c(c1)C(=O)C(=O)C1=C2OC2(CCN(Cc3ccc(F)cc3)CC2)CS1

Procedure:
Compound 154 was synthesized using 8-methoxyspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-4-fluorobenzene ad conditions outlined in procedure W. Mp.=219-221° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.64 (d, J=8.4 Hz, 1H), 7.37-7.27 (m, 4H), 7.15 (dd, J=8.8, 8.8 Hz, 2H), 3.88 (s, 3H), 3.54 (s, 2H), 3.05 (s, 2H), 2.69 (d, J=11.6 Hz, 2H), 2.36 (dd, J=10.4 Hz, 2H), 1.98 (d, J=13.2 Hz, 2H), 1.81 (dd, J=10.4, 10.4 Hz, 2H); LCMS: 440 [M+H].
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>S(Cl)(Cl)=O.ClCCl>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]([O:23][CH3:24])=[O:22])=[O:6]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)c1c(F)ccc([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 22 h
Yield: 83 %

Procedure:
A solution of 1.82 g (8.94 mmol) of 2,6-difluoro-3-nitrobenzoic acid in 36 ml of thionyl chloride was refluxed for three and a half hours. The reaction medium was concentrated and was co-evaporated twice with toluene. The residue obtained was dissolved in 50 ml of dichloromethane under nitrogen. 1.48 g (8.94 mmol) of methyl (S)-pyrrolidine-2-carboxylate hydrochloride were added and the reaction medium was cooled to 0° C. 2.75 ml (19.67 mmol, 2.2 eq) of triethylamine were then added dropwise. After 22 hours, a saturated aqueous sodium hydrogen carbonate solution was added. The organic phase was again washed with a saturated aqueous sodium hydrogen carbonate solution and then twice more with a 1 M aqueous hydrochloric acid solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 2.52 g were obtained. Yield=83%.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:30])[C@:4]1([OH:29])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][CH2:27][OH:28].[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3](=[O:30])[C@:4]1([OH:29])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][CH2:27][O:28][S:32]([CH3:31])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCO)[C@]2(O)C(=O)CCl
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOS(C)(=O)=O)[C@]2(O)C(=O)CCl

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-(2-hydroxyethoxy)pregna-1,4-diene-3,20-dione (7.6 mmoles) in 30 ml of pyridine is cooled to 0°C and 1 ml of methanesulfonyl chloride is added. After 2 hours the mixture is poured into cold dilute hydrochloric acid and extracted with chloroform. The chloroform solution is dried and evaporated in vacuo to yield the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([O:22][C:23]([NH:25][C@@H:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([O:1][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:26]([NH:25][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[C:27]([O:29][CH3:30])=[O:28])=[CH:37][CH:36]=2)[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(OC2CCN(C(=O)OCc3ccccc3)CC2)cc1)NC(=O)OC(C)(C)C
Reaction time: 15 h

Procedure:
18.9 g (86.2 mmol) of benzyl 4-hydroxypiperidine-1-carboxylate, 25.4 g (86.2 mmol) of methyl (2S)-2-(t-butoxycarbonylamino)-3-(4-hydroxyphenyl)propionate and 27.1 g (103.4 mmol) of triphenylphosphine were dissolved in 500 ml of tetrahydrofuran. 37.5 g (86.2 mmol) of diethyl azodicarboxylate was added to the solution at room temperature, and they were stirred for 15 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the crude product was obtained, which was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)[CH:8]=[N:7][CH:6]=1.[ClH:22]>>[ClH:22].[CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][C:3]([OH:21])=[O:2])=[CH:6][N:7]=[CH:8]1
Reactant: COC(=O)Cc1cncn1Cc1ccc2ccccc2c1
Agent: Cl
Product: O=C(O)Cc1cncn1Cc1ccc2ccccc2c1
Temperature: 55 °C

Procedure:
2-[1-(Naphth-2-ylmethyl)-1H-imidazol-5-yl]acetic acid methyl ester (0.92 g, 3.28 mmol ) was dissolved in 2.5m hydrochloric acid (50 ml ) and heated at 55° C. for 3 h. After this time, the solution was evaporated in vacuo to give the title compound as a white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Temperature: 0 °C
Yield: 86.5 %

Procedure:
To a solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (5 g, 24.84 mmol, 1.0 equiv) in DCM (125 mL) was added Dess-Martin periodinane (11.59 g, 27.33 mmol, 1.1 equiv) at 0° C. in a few portions. The solution was stirred at 0° C. for a while and allowed to warm to room temperature slowly. The solution was stirred at room temperature for 18 hrs. A lot of white solid suspended. The white solid was removed by filtration, eluted with EtOAc (100 mL). The combined organic phase was washed with saturated solution of NaHCO3 (50 mL), dried over anhydrous Na2SO4, concentrated to afford 4.28 g (yield 86%) of tert-butyl 3-oxopiperidine-1-carboxylate as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH:22]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH2:23][C:24](OCC)=[O:25])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[Cl-].[NH4+]>CCOCC.C(OCC)(=O)C.CCCCCC>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH:22]([C:29]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=2[F:36])[CH2:23][CH2:24][OH:25])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
Process 1: At 0° C., lithium aluminum hydride (a 1.0M tetrahydrofuran solution, 6.74 ml, 6.74 mmol) was added dropwise to a tetrahydrofuran solution (10 ml) of the ethyl 3-[(4-chlorophenyl)sulfonyl]-3-(2,5-difluorophenyl)propionate (1.31 g, 3.37 mmol) obtained in Example 25. The mixture was then was stirred at room temperature for 3 hours. After cooling the reaction mixture to 0° C., and addition of a saturated aqueous ammonium chloride solution, the mixture was stirred at room temperature for 15 hours. The solid thus precipitated was filtered off. The solution thus obtained was diluted with ether, washed with brine, dried over magnesium sulfate and then, concentrated. The residue thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (397 mg, 1.14 mmol, 34%) was obtained as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10](Cl)[N:9]=2)[CH2:5][O:4][CH2:3]1.[S:20]1(=[O:31])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][NH:23][CH2:22][CH2:21]1>C(O)CCC>[NH2:1][C:2]1([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]=[C:10]([N:23]3[CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:20](=[O:31])[CH2:21][CH2:22]3)[N:9]=2)[CH2:5][O:4][CH2:3]1
Reactant: O=S1CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(NCC3(N)COC3)c2c1
Solvent: CCCCO
Product: Cc1ccc2nc(N3CCS(=O)c4ccccc4C3)nc(NCC3(N)COC3)c2c1
Temperature: 160 °C

Procedure:
A mixture of N-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine (140 mg, 0.5 mmol) and 2,3,4,5-tetrahydro-1,4-benzothiazepine 1-oxide (270 mg, 1.5 mmol) in n-butanol (10 mL) was heated at 160° C. for 30 minutes. After the resulting mixture was concentrated in vacuo, the residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 424, 1H NMR (400 MHz, CD3OD) δ ppm 8.01 (s, 1 H), 7.83-7.79 (m, 2 H), 7.66-7.52 (m, 4 H), 5.45-5.41 (d, 1 H), 5.10 (brs, 1 H), 4.80-4.72 (m, 6 H), 4.39 (s, 2 H), 3.51 (s, 2 H), 2.45 (s, 3 H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[CH:17]=[O:18].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:51]1[CH:52]=[C:53]([NH:57][C:58](=[O:63])[CH2:59][CH:60]([CH3:62])[CH3:61])[CH:54]=[N:55][CH:56]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].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.O.CN(C=O)C>[CH:17]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:51]3[CH:52]=[C:53]([NH:57][C:58](=[O:63])[CH2:59][CH:60]([CH3:61])[CH3:62])[CH:54]=[N:55][CH:56]=3)[CH:3]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=1)=[O:18]
Reactant: O=Cc1nn(C2CCCCO2)c2ccc(I)cc12
Reactant: CC(C)CC(=O)Nc1cncc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(=O)Nc1cncc(-c2ccc3c(c2)c(C=O)nn3C2CCCCO2)c1
Temperature: 90 °C

Procedure:
A solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carbaldehyde (II) (498 mg, 1.4 mmol), bis(pinacolato)diboron (426 mg, 1.6 mmol), KOAc (412 mg, 4.2 mmol) and dry DMF (10 mL) was purged with nitrogen. Pd(dppf)2Cl2 (68 mg, 0.08 mmol) was added to the reaction and purged again with nitrogen. The solution was heated at 90° C. for 2 h. Once TLC showed the disappearance of (II), the solution was cooled to room temperature. To this solution was added K3PO4 (446 mg, 2.1 mmol), N-(5-bromopyridin-3-yl)-3-methylbutanamide (XXVIII) (358 mg, 1.4 mmol), Pd(PPh3)4 (48 mg, 0.042 mmol) and water (2 mL). The solution was purged with nitrogen and heated at 90° C. for 4 h. The reaction was passed through a pad of Celite® and then concentrated under reduced pressure. The residue was suspended in water, sonicated, filtered and dried. The crude product was purified on a silica gel column (100% DCM→3:97 MeOH:DCM) to give N-(5-(3-formyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide (LXXXIV) as an off white solid (239 mg, 0.59 mmol, 42% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 0.96 (d, 6H), 1.60-1.67 (m, 1H), 1.75-1.84 (m, 1H), 2.05-2.15 (m, 3H), 2.26 (d, 2H), 2.39-2.47 (m, 1H), 3.80-3.86 (m, 1H), 3.89-3.93 (m, 1H), 6.13 (dd, 1H), 7.91 (dd, 1H), 8.06 (d, 1H), 8.36 (s, 1H), 8.39 (s, 1H), 8.63 (d, 1H), 8.81 (d, 1H), 10.23 (s, 1H); ESIMS found C23H26N4O3 m/z 407.3 (M+H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24](Cl)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[C:40](B(O)O)[CH:39]=[CH:38][N:37]=1>C(COC)OC>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:40]3[CH:39]=[CH:38][N:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=3)=[N:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(c1ccc(Oc2nccnc2-c2ccnc(C(F)(F)F)c2)cc1)c1nc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of (1H-benzo[d]imidazol-2-yl)(4-(3-chloropyrazin-2-yloxy)phenyl)methanone (300 mg, 0.855 mmol), potassium phosphate (545 mg, 2.57 mmol), 2-(trifluoromethyl)pyridin-4-ylboronic acid (490 mg, 2.57 mmol), and Bis-[4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine]palladium dichloride (121 mg, 0.171 mmol) in dimethoxyethane was heated to 80° C. Following complete reaction, the mixture was cooled to room temperature which caused a solid to precipitate which was collected by filtration and dried to give (1H-benzo[d]imidazol-2-yl)(4-(3-(2-(trifluoromethyl)pyridin-4-yl)pyrazin-2-yloxy)phenyl)methanone. MS (ESI, pos. ion) m/z: 461.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)(C)(C)C>O1CCOCC1>[F:18][C:15]([F:16])([F:17])[CH2:14][N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(F)(F)F)CC1
Solvent: C1COCCO1
Product: NC1CCN(CC(F)(F)F)CC1
Reaction time: 1.5 h

Procedure:
[1-(2,2,2-Trifluoroethyl)piperidin-4-yl]-carbamic acid tert-butyl ester was then taken up in dioxane (80 mL) and hydrogen chloride gas was bubbled through the solution for 10 minutes. The reaction vessel was capped tightly and stirred for 1.5 hours. The solvent was removed under reduced pressure at 40° C. The residue was taken up in 42 mL of 0.5M sodium methoxide in methanol, stirred at room temperature for 3 hours, and filtered. The filtrate was concentrated, taken up in ethyl acetate, filtered, and concentrated to give 1.0 g of 1-(2,2,2-trifluoroethyl)piperidin-4-ylamine as a dark colored oil, (M+H)+=183.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=3)=[O:23])[CH:18]=[CH:17][C:15]=2[N:16]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22]([NH:21][C:19]2[CH:18]=[CH:17][C:15]3[N:16]=[C:12]([NH:11][C:2]4[N:10]=[CH:9][N:8]=[C:7]5[C:3]=4[N:4]=[CH:5][NH:6]5)[S:13][C:14]=3[CH:20]=2)=[O:23])=[CH:26][C:27]=1[C:32]([F:34])([F:33])[F:35]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Nc1nc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2s1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc2nc(Nc3ncnc4[nH]cnc34)sc2c1

Procedure:
1-(4-Chloro-3-trifluoromethylphenyl)-3-[2-(9H-purin-6-ylamino)-benzothiazol-6-yl]urea was prepared from 6-chloropurine (17 mg, 0.11 mmol) and 1-(2-aminobenzothiazol-6-yl)-3-(4-chloro-3-trifluoromethylphenyl)urea (Intermediate 3, 42.5 mg, 0.11 mmol) according to GP 1. The reaction mixture was purified by pTLC (dichloromethane:methanol=9:1) to yield a yellow solid (35.4 mg, 70 μmol, 64%). LC/ESI-MS: m/z=505 [M(35Cl)+H]+; m/z=503 [M(35Cl)−H]−; Rt=3.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][C@H:18]([OH:20])[CH2:19][C@H:13]3[CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[H-].[Na+].I[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]3[CH2:17][C@H:18]([O:20][CH2:28][CH3:29])[CH2:19][C@H:13]3[CH2:12]2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=S(=O)(c1ccc(Cl)c(C(F)(F)F)c1)N1CCN2C[C@H](O)C[C@H]2C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCO[C@@H]1C[C@H]2CN(S(=O)(=O)c3ccc(Cl)c(C(F)(F)F)c3)CCN2C1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To (7R,8aS)-2-{[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}octahydropyrrolo[1,2-a]pyrazin-7-ol (0.3 mmol, Example 187) in tetrahydrofuran (1 mL) at room temperature was added NaH (20 mg, 60% in mineral oil). After 15 minutes, iodoethane (0.39 mmol) was added. The mixture was stirred at 60° C. for 2 days. The mixture was partially purified by chromatography on silica gel (CH2Cl2/CH3OH=10:1) to give the title compound as an impure solid (77 mg). The product was purified by HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol (70:30 to 0:100 gradient over 16 minutes), flow rate 36 mL/minute, UV=220 nm) to give the title compound (20 mg, 16% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (m, 3H), 1.47 (m, 1H), 1.73 (m, 1H), 2.00 (m, 1H), 2.08 (m, 1H), 2.19 (m, 1H), 2.39 (m, 6H), 2.93 (m, 1H), 3.63 (m, 1H), 3.76 (m, 1H), 3.92 (m, 1H), 8.04 (m, 3H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][N:5]=[CH:6][C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13].CON(C(C)=O)[C:34](=[O:36])[CH3:35]>CN(C)C=O.CO>[C:34]([NH:1][CH2:2][CH2:3][O:4][N:5]=[CH:6][C:7]1[C:8]([F:30])=[C:9]([F:29])[C:10]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=2[F:28])=[C:11]([CH:19]=1)[C:12]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:13])(=[O:36])[CH3:35]
Reactant: CON(C(C)=O)C(C)=O
Reactant: NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)NCCON=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.8 %

Procedure:
To a solution of 5-[(2-amino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.14 mg, 0.02 mmol) described in Example 22 in a mixture of dimethylformamide (1 ml) and methanol (5 ml), N-methoxy-diacetamide (100 mg, 0.76 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was purified with Mega Bond Elut silica gel (5 g, Varian, Inc.). From the fractions eluted with 6% methanol/methylene chloride, 5-[(2-acetylamino-ethoxyimino)-methyl]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide (8.10 mg, 92% yield) was obtained as a pale yellow solid.