Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:6]1[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=1)[CH2:3][C:4]#[CH:5].[N:12]([CH2:15][C:16]1[CH:20]=[CH:19][O:18][CH:17]=1)=[N+:13]=[N-:14]>>[ClH:1].[O:18]1[CH:19]=[CH:20][C:16]([CH2:15][N:12]2[CH:5]=[C:4]([CH2:3][CH2:2][C:6]3[N:7]=[C:8]([NH2:11])[NH:9][CH:10]=3)[N:14]=[N:13]2)=[CH:17]1
Reactant: C#CCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccoc1
Agent: Cl
Product: Nc1nc(CCc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 53.9 %

Procedure:
4-But-3-ynyl-1H-imidazol-2-ylamine hydrochloride (0.066 g, 0.384 mmol) was reacted with 3-azidomethyl-furan (0.057 g, 0.461 mmol) following the general procedure for click reactions outlined above to produce 4-[2-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-ethyl]-1H-imidazol-2-ylamine hydrochloride (0.061 g, 54%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.61 (s, 1H), δ 7.46 (s, 1H), δ 6.42 (s, 1H), δ 6.38 (s, 1H), δ 5.41 (s, 2H), δ 2.95 (t, 2H), δ 2.83 (t, 2H) ppm; 13C (75 MHz, CD3OD) δ 146.3, 144.2, 141.6, 141.5, 126.5, 122.3, 120.2, 109.9, 109.1, 44.8, 24.2, 23.9 ppm; HRMS (ESI) calcd for C12H14N6O (M+) 259.1301. found 259.1306.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.C([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)CCC>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([N:27]([CH:12]([CH3:13])[CH2:11][CH2:15][CH3:14])[C:24]2[CH:23]=[CH:22][CH:21]=[CH:26][CH:25]=2)[N:3]=1
Reactant: CCCCc1ccc(N)cc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CCCC(C)N(c1ccccc1)c1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(4-pentyl)phenylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-butylphenylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([O:37][CH3:38])[CH:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:38][O:37][C:33]1[CH:32]=[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][N:34]=1
Reactant: COc1cc(Cl)ccn1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: OCCO
Product: COc1cc(N2CCN(C(=O)c3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)ccn1

Procedure:
In the manner given in Example 5, a mixture of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 4-chloro-2-methoxypyridine and triethylamine is heated in ethylene glycol at 80° C. to give 1-(2-methoxypyridin-4-yl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:9][C:5]1[N:4]=[N:3][C:2]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]([CH3:8])[CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1cc(Cl)nnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1nnc(Cl)cc1C
Temperature: 110 °C
Reaction time: 4 h
Yield: 25.8 %

Procedure:
A mixture of 4.29 g of 3,6-dichloro-4-methylpyridazine, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 4 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 7.08 g of the resultant residue was subjected to silica gel column chromatography, to obtain 1.95 g of diethyl (6-chloro-4-methyl-3-pyridazinyl)malonate.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:17][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=1
Reactant: OCc1ccc(-c2ccccc2)nc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
(6-Phenylpyridin-3-yl)methanol (15.0 g) synthesized in Reference Example 20 was dissolved in dichloromethane (150 mL) and, after ice-cooling, thionyl chloride (12.5 g) was added to, and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (13.5 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:38]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][Br:38])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(CO)c2c1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(CBr)c2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 0.200 g (0.855 mmol) 4-hydroxymethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester (Example 92, Step 2) in 5 mL of THF was added 0.336 g (1.28 mmol) of triphenylphosphine and 0.355 g (1.07 mmol) of carbon tetrabromide. The reaction was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was diluted ith 20 mL of ether and filtered. The filtrate was concentrated in vacuo and chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.196 g of 4-bromomethyl-3-methylbenzofuran-2-carboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[N:5]([CH3:7])[CH:6]=1.[N:9]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[CH:26][C:25]4=[CH:28][CH:29]=[C:30](B5OC(C)(C)C(C)(C)O5)[N:24]4[N:23]=3)=[CH:17][CH:16]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[CH3:7][N:5]1[CH:6]=[C:2]([C:30]2[N:24]3[C:25]([CH:26]=[N:27][C:22]([NH:21][C:18]4[CH:19]=[CH:20][C:15]([N:9]5[CH2:14][CH2:13][O:12][CH2:11][CH2:10]5)=[CH:16][CH:17]=4)=[N:23]3)=[CH:28][CH:29]=2)[N:3]=[C:4]1[CH3:8]
Reactant: Cc1nc(Br)cn1C
Reactant: CC1(C)OB(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)OC1(C)C
Product: Cc1nc(-c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cn1C

Procedure:
[7-(1,2-Dimethyl-1H-imidazol-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from 4-bromo-1,2-dimethyl-1H-imidazole and (4-morpholin-4-yl-phenyl)-[7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine in an analogous manner to Example 1042b. Product isolated as a yellow solid (11 mg, 10%). m.p.=decomposed at 250° C.; LCMS (m/e) 390 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.85 (s, 1H), 7.55 (d, 2H, J=8.9 Hz), 7.27-7.23 (m, 1H), 6.97 (d, 2H, J=8.9 Hz), 6.81 (d, 1H, J=4.8 Hz), 6.56 (bs, 1H), 3.93-3.87 (m, 4H), 3.64 (s, 3H), 3.18-3.12 (m, 4H), 2.46 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[CH3:13][S:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=2)=[NH:8])=[CH:17][CH:16]=1
Reactant: CSc1ccc(N)cc1
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Product: CSc1ccc(NC(=N)c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethylbenzonitrile (0.62 g, 3.6 mmol) and 4-methylthioaniline (0.5 g, 3.6 mmol) by following the procedure described in preparation 1, (0.495 g, 44.4%, purity 98.3% by HPLC), mp 144-146° C. 1H-NMR (CDCl3):δ 2.49 (s, 3H), 4.8 (bs, 2H), 6.93-6.95 (d, 2H), 7.26-7.32 (m, 2H), 7.70-7.72 (d, 2H), 7.99-8.01 (d, 2H). MS m/z:311.1(M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O.[NH2:18][NH2:19]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[NH:19][N:18]=1
Reactant: CCCCCCC(=O)CC(=O)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCCCc1cc(-c2cccs2)n[nH]1
Yield: 59.5 %

Procedure:
In ethanol (20 ml), 1-(2-thienyl)-1,3-nonanedione (1.30 g) and hydrazine hydrate (1.26 g) are refluxed for 3 hours by heating. After the reaction is completed, the solvent is distilled off. The obtained residue is added to petroleum ether and crystallized to obtain the objective 3-(2-thienyl)-5-n-hexylpyrazole (0.76 g) as colorless crystals. mp. 53-55° C.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)[CH:7]=[CH:6][C:5]=12.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.O>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=3)=[O:15])[CH:7]=[CH:6][C:5]=12
Reactant: O=C(O)c1cccnc1Oc1ccc2nsnc2c1
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3nsnc3c2)cc1
Temperature: 25 °C
Yield: 63.6 %

Procedure:
2-(Benzo[2,1,3]thiadiazol-5-yloxy)-nicotinic acid (30.8 mg, 0.11 mmol), 2-(4-aminomethyl-phenyl)-propan-2-ol (18.6 mg, 0.11 mmol), 1-hydroxybenzotriazole hydrate (16.8 mg, 0.12 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (25.9 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (10 ml) and stirred at room temperature over night. The solution was poured into water (30 ml) and extracted with ethyl acetate. The combined organic layers were washed successively with 1N NaOH, water, and brine, then dried over sodium sulfate and concentrated in vacuo. The resulting amber oil was purified by flash column chromatography (1:1 ethyl acetate/hexane) to afford a white foam (29 mg, 0.07 mmol).
Reaction SMILES: [C:1]([OH:11])(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl>[Br-].C([N+](CC)(CC)CC)C.O>[C:1]([O:11][CH2:12][CH:14]1[O:16][CH2:15]1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: ClCC1CO1
Agent: CC[N+](CC)(CC)CC
Agent: [Br-]
Solvent: O
Product: O=C(C=Cc1ccccc1)OCC1CO1
Temperature: 110 °C

Procedure:
To 7.5 g of trans-cinnamic acid (manufactured by Wako Pure Chemical) were added 3 g of tetraethylammonium bromide (manufactured by Wako Pure Chemical) and 100 ml of epichlorohydrin (manufactured by Wako Pure Chemical), the mixture was heated to reflux at 110° C. for 3 hours, 50 ml of distilled water was added thereto, an organic layer was separated, concentrated in vacuo at 80° C. and distilled under reduced pressure of 6 mmHg and the fraction of 130 to 160° C. was recovered to give 12 g of glycidyl cinnamate. An epoxy equivalent of this glycidyl cinnamate was 240.3.
Reaction SMILES: [H-].[Na+].[CH2:3]([P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])P(=O)(OCC)OCC.[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44]([CH:46]=O)=[CH:45][C:23]=2[N:22]=1>C1COCC1>[NH2:20][C:21]1[C:30]2[N:29]=[CH:28][C:27]([CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=3[CH3:41])=[CH:26][C:25]=2[C:24]2[CH:42]=[CH:43][C:44](/[CH:46]=[CH:3]/[P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])=[CH:45][C:23]=2[N:22]=1
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of NaH (1.2 equiv.) in THF (0.1 M) cooled at 0° C. was added a solution of tetraethyl methylenediphosphonate (1.3 equiv.) in THF (0.21 M). To the resulting reaction mixture was added a solution of 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (2-2) (Example 9—Step 1) (1.0 equiv.) in THF (0.08 M). The reaction was stirred at room temperature for 30 minutes, then solvents were removed in vacuo, and the resulting residue was purified by a COMBIFLASH® system (ISCO) using a gradient of 0-5% MeOH/DCM to provide (E)-diethyl 2-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)vinylphosphonate (3-1) as a colorless solid.
Reaction SMILES: [CH3:1][C:2]([CH3:54])([CH2:7][CH2:8][C:9](=[O:53])[N:10]([CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:47])[NH:19][C:20]2[S:21][C:22]3[CH2:46][CH2:45][CH2:44][CH2:43][C:23]=3[C:24]=2[C:25](=[O:42])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)=[CH:29][CH:28]=2)[CH:13]=1)[C:3]([O:5][CH3:6])=[O:4].[CH2:55]=O>>[CH3:54][C:2]([CH3:1])([CH2:7][CH2:8][C:9]([N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:47])[NH:19][C:20]2[S:21][C:22]3[CH2:46][CH2:45][CH2:44][CH2:43][C:23]=3[C:24]=2[C:25](=[O:42])[NH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][N:39]([CH3:55])[CH2:40][CH2:41]3)=[CH:31][CH:32]=2)[CH:13]=1)[CH:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[O:53])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=O
Reactant: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCN4CCNCC4)cc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC
Product: CCC(CC)N(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCCN4CCN(C)CC4)cc2)CCCC3)c1)C(=O)CCC(C)(C)C(=O)OC

Procedure:
By using 180 mg of methyl 2,2-dimethyl-5-oxo-5-[pentan-3-yl(3-{[3-({4-[3-(piperazin-1-yl)propyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}benzyl)amino]pentanoate and 0.06 mL of a 37% aqueous formalin solution, the reaction similar to Preparation Example 14 was performed, thereby obtaining 152 mg of methyl 2,2-dimethyl-5-[(3-{[3-({4-[3-(4-methylpiperazin-1-yl)propyl]phenyl}carbamoyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]carbamoyl}benzyl)(pentan-3-yl)amino]-5-oxopentanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)[CH:18]=2)[NH:13][CH:12]=1)[CH2:9][NH2:10].O=[CH:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.O1CCOCC1>O1CCOCC1.C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:11]2[C:19]3[C:14](=[CH:15][C:16]([CH3:27])=[C:17]([O:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)[CH:18]=3)[NH:13][C:12]=2[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:10][CH:9]=1
Reactant: CCOC(=O)C=O
Reactant: Cc1cc2[nH]cc(C(CN)c3ccccc3F)c2cc1Oc1cncnc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(C)c(Oc3cncnc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of 2-(2-fluorophenyl)-2-(6-methyl-5-(pyrimidin-5-yloxy)-1H-indol-3-yl)ethanamine (0.262 g, 0.724 mmol) and 50% ethyl 2-oxoacetate in toluene (0.316 mL, 1.593 mmol) in 1,4-dioxane (18.10 mL) under nitrogen was added 4 N HCl/1,4-dioxane (0.543 mL, 2.172 mmol). After stirring overnight, the reaction was concentrated in vacuo and dissolved in water. Saturated aqueous NaHCO3 was added until pH ˜12 by litmus paper. The solution was extracted with EtOAc (2×). After separation of the layers, the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give crude product which was used in subsequent step. This was added to 10% Pd/C (0.770 g, 0.724 mmol) in toluene (10.34 mL), and the reaction was refluxed for 45 min. After cooling to room temperature, the reaction was filtered through a pad of CELITE® and rinsed with EtOAc. The filtrate was concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 40 g column eluting with 0-2% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0716 g, 0.162 mmol, 22.4% yield) as a tan solid.
Reaction SMILES: [OH-].[Na+].[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O.CC(C)=O>[CH2:12]([O:6][C:5]1[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=1[CH:3]=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1ccccc1OCc1ccccc1
Yield: 132.9 %

Procedure:
Sodium hydroxide (20.0 gms.; 0.5 mole) was dissolved in 150 ml H2O and salicylaldehyde (53.2 ml; 0.5 mole) dissolved in 200 ml acetone was added, followed by benzyl bromide (65.4 ml; 0.55 mole) dissolved in 200 ml acetone. The reaction mixture was refluxed for a period of 24 hours and allowed to cool. The acetone was evaporated in vacuum and the two phase residue extracted with 300 ml CH2Cl2. The CH2Cl2 layer was washed with 150 ml H2O and dried over anhydrous Na2SO4. The Na2SO4 was filtered off and the solvent removed from the filtrate to yield 141 grams of the crude product.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.Cl[C:16]1[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1>>[F:23][C:22]([F:25])([F:24])[C:20]1[CH:19]=[CH:18][N:17]=[C:16]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)[N:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: NC1CCN(c2nccc(C(F)(F)F)n2)CC1

Procedure:
The title compound was prepared from D7 and 2-chloro-4-trifluoromethyl-pyrimidine using the procedure outlined for Descriptions D11 and D12.
Reaction SMILES: O[CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:26][CH2:25]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:7])[CH3:6].[N-:27]=[N+:28]=[N-:29].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[N:27]([CH2:2][C@@H:3]([NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:13]([O:22][CH2:23][CH:24]2[CH2:25][CH2:26]2)[N:12]=1)=[O:10])[CH2:4][CH:5]([CH3:6])[CH3:7])=[N+:28]=[N-:29]
Reactant: CC(C)C[C@@H](CO)NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C[C@@H](CN=[N+]=[N-])NC(=O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.5 %

Procedure:
To a colorless solution of 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (Example 14b; 231 mg, 639 μmol) in DMF (25.6 mL) and CCl4 (6.4 mL) was added sodium azide (49.9 mg, 767 μmol) and triphenylphosphine (352 mg, 1.34 mmol). The resulting reaction mixture was stirred at 90° C. for 4 hours. After cooling to room temperature the solvent was removed in vacuo. The residue was partitioned between water and ethyl acetate; the organic phases were washed with brine, combined, dried with Na2SO4, filtered and concentrated in vacuo. The residue, a brown waxy solid, was purified by flash chromatography (silica gel, 50 g, 0% to 60% ethyl acetate in heptane) to give the title compound (110 mg, 45%) as white solid; MS (ESI) 387.3 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[C:23]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[C:15]2[CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[Cl:22])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCNc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Dissolve 6-(2-amino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.208 mmol) in DCM (4 mL). Add benzoyl chloride (24 μL, 0.208 mmol), and triethylamine (44 μL, 0.312 mmol) and stir at ambient temperature for 24 h under nitrogen atmosphere. Dilute with DCM and add 1M aqueous HCl. Extract the aqueous layer with DCM. Dry the organic layer over MgSO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to obtain 6-(2-benzoylamino-ethylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][S:18][CH3:19].ClN1C(=O)CCC1=O.C[O-].[Na+].CO>C(Cl)Cl>[CH2:1]([O:8][C:9]1[N:14]=[C:13]([N:15]=[S:18]([CH3:19])[CH3:17])[C:12]([F:16])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: Nc1nc(OCc2ccccc2)ncc1F
Agent: C[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CS(C)=Nc1nc(OCc2ccccc2)ncc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93 %

Procedure:
A 10 mL oven-dried Schlenk flask was charged with 2-(benzyloxy)-5-fluoropyrimidin-4-amine (101 mg, 0.462 mmol), CH2Cl2 (2 mL), and dimethylsulfide (75.0 μL, 1.02 mmol) and was cooled to 0° C. in an ice bath. N-Chlorosuccinimide (122 mg, 0.914 mmol) was added and the resulting mixture was allowed to stir at 0° C. for 45 minutes, and then at room temperature for 30 minutes. A solution of NaOMe in MeOH (25%, 360 μL, 1.35 mmol) was added. After 20 minutes, the reaction was quenched with water (3 mL) and allowed to stir for 1 hour. The crude reaction mixture was then diluted with CH2Cl2 and washed with water (50 mL×2), dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation and then on high vacuum to give the title compound (120 mg, 93%) as an off white solid: mp 125-129° C.; 1H NMR (300 MHz, DMSO-d6): δ 7.70 (d, J=3.9 Hz, 1H), 7.25-7.44 (m, 5H), 5.21 (s, 2H), 2.75 (s, 6H); MS (ESI) m/z 281.1 (M+H)+. *Yamamoto, Y.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 4128-4129.
Reaction SMILES: [C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=S)[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:20][NH2:21]>CO>[C:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]([NH:20][NH2:21])[CH2:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: S=C1CN=C(c2ccccc2)c2ccccc2N1
Solvent: CO
Solvent: O
Product: NNC1=Nc2ccccc2C(c2ccccc2)=NC1

Procedure:
A stirred mixture of 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-thione (7.45 g., 0.03 mole) in methanol (300 ml.) was allowed to react with hydrazine hydrate (6.0 g., 0.12 mole) to give 5-phenyl-3H-1,4-benzodiazepin-2-yl hydrazine as an oil. A solution of thio material in tetrahydrofuran (75 ml.) was cooled in an ice bath and treated with a solution of chloroacetyl chloride (3.39 g., 0.03 mole) in tetrahydrofuran (25 ml.) to give 6.43 g. of chloroacetic acid, 2-(5-phenyl-3H-1,4-benzodiazepin-2-yl) hydrazide (A).