Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([Cl:17])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]([O:15][CH3:16])[N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=2)[CH:12]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1c2cc(Cl)ccc2nn1CC(C)(N)C#N
Product: COc1c2cc(Cl)ccc2nn1CC(C)(C#N)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-chloro-3-methoxy-2H-indazol-2-yl)-2-methylpropionitrile (57 mg, described in Example 107) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (96 mg, 95%). MS (ES): M/Z [M+H]=469. 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 4.19 (s, 3H), 4.77 (d, 1H), 4.90 (d, 1H), 7.16 (d, J=9.2 Hz, 1H), 7.46 (d, J=9.4 Hz, 1H), 7.87 (d, J=8.0 Hz, 2H), 7.92-8.01 (m, 3H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.9 (s, 3F).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>N1C=CC=CC=1>[C:24]1([CH3:25])[CH:26]=[CH:27][C:21]([S:18]([O:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH:11]=2)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: CCCCCCc1ccc(CCCCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCCCCCc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 26.7 %

Procedure:
4-(4-Hexylphenyl)butanol (5.0 g) was dissolved in 20 ml of pyridine and 4.88 g of tosyl chloride was added thereto. The reaction mixture was left standing at room temperature overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with 2 N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and saturated brine in order and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:7) to give 2.21 g of 4-(4-hexylphenyl)butyl p-toluenesulfonate as a colorless, oily substance.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][O:4][C:5](=[O:10])[CH2:6][C:7](=O)[CH3:8].[CH3:11][O:12][C:13](=[O:16])[C:14]#[CH:15]>CO>[CH3:11][O:12][C:13](=[O:16])[CH:14]=[CH:15][C:6](=[C:7]([NH:2][CH3:1])[CH3:8])[C:5]([O:4][CH3:3])=[O:10]
Reactant: CN
Reactant: COC(=O)CC(C)=O
Reactant: C#CC(=O)OC
Solvent: CO
Product: CNC(C)=C(C=CC(=O)OC)C(=O)OC
Temperature: 90 °C
Yield: 11.4 %

Procedure:
Methylamine (20 mL, 40 mmol, 2 M in THF) was dissolved in MeOH (130 mL). 3-Oxo-butyric acid methyl ester (5.7 mL, 48 mmol) was added, and the mixture was heated at 90° C. for 3 h in a sealed tube. After cooling the mixture to r.t., propynoic acid methyl ester (5.3 mL, 60 mmol) was added. The resulting mixture was then refluxed for 48 h. After cooling to r.t., the solvent was evaporated, and the crude residue was purified by silica gel chromatography (0-50% EtOAc/hexanes) to give 0.97 g of the title compound as a light yellow solid. 1H NMR (CDCl3, 200 MHz): δ=10.55 (br s, 1H), 7.75 (d, 1H, J=15.4 Hz), 6.06 (d, 1H, J=15.4 Hz), 3.75 (s, 3H), 3.72 (s, 3H), 3.04 (d, 3H, J=4.8 Hz), 2.26 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.[C:24]([CH2:27][C:28](=O)[CH3:29])(=[O:26])[CH3:25]>C(O)(C)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:4]=3)[N:1]=[C:28]([CH3:29])[C:27]=2[C:24](=[O:26])[CH3:25])=[CH:18][CH:19]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Product: CC(=O)c1c(C)nc2ccc(Oc3ccccc3)cc2c1-c1ccc(Cl)cc1
Reaction time: 16.5 h
Yield: 42 %

Procedure:
The title compound was prepared from (2-Amino-5-phenoxy-phenyl)-(4-chloro-phenyl)-methanone [example A5] and acetylacetone according to the method of example 1, except that the solvent was isopropanol, the reaction time was of 16.5 h and the residue was purified by spontaneous crystallization from the reaction mixture. Yield: 42%; MS: m/z=387 (M).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH3:27])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1C#N
Temperature: 25 °C

Procedure:
A mixture of 0.34 g (0.92 mMol) of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylthio)phenyl]-2-oxo-pyridine-3-carbonitrile (Step 3) in 10 ml of DMF and 0.33 g of K2CO3 and 2 ml of iodomethane, was stirred at room temperature over the weekend. The reaction mixture was diluted with 75 ml of water and extracted with dichloromethane (4×25 ml). The combined organic layers were extracted once with 50 ml of 10% NaOH solution then once with brine, dried over MgSO4 and evaporated to dryness. The residue was purified by HPLC to give two fractions. The first fraction was the desired product: m.p. 202.5°-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN(C)[CH:15]=[O:16].Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][O:2][C:3]1[S:4][C:5]([CH:15]=[O:16])=[CH:6][CH:7]=1
Reactant: COc1cccs1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1ccc(C=O)s1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.4 %

Procedure:
To a solution of 2-methoxythiophene (79 mg, 0.69 mmol) in 3.5 mL of 9:1 tetrahydrofuran/hexamethylphosphoramide under argon at −78° C. was added n-butyllithium (0.30 mL, 2.5 M in hexanes) dropwise. After stirring at −78° C. for 20 minutes, dimethylformamide (0.27 mL, 3.5 mmol) was added in a single portion and the reaction mixture allowed to warm to room temperature while stirring, before being poured into 25 mL of 1 N hydrochloric acid. Organics were extracted with ether (2×25 mL), dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (10-12% ethyl acetate in hexanes) to give 5-methoxy-2-thiophenecarbaldehyde (71 mg, 72%). Used without further characterization.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:10]([N:12]([CH2:15][CH2:16][N:17]=[C:18]=[S:19])[CH2:13][CH3:14])[CH3:11]>>[CH2:10]([N:12]([CH2:13][CH3:14])[CH2:15][CH2:16][NH:17][C:18]([NH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[S:19])[CH3:11]
Reactant: CCN(CC)CCN=C=S
Reactant: NCCN1CCCCC1
Product: CCN(CC)CCNC(=S)NCCN1CCCCC1

Procedure:
By the general method described in Example 1, 1-(2-aminoethyl)-piperidine is reacted with diethylaminoethyl isothiocyanate to give the title compound.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH2:38][C:39]([NH2:41])=[O:40]>>[NH2:41][C:39](=[O:40])[CH2:38][CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:30]=[CH:31][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:27][C:28]=1[CH3:35])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCCC(N)=O
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Product: CON=C1C[C@@H](C(=O)NCCC(N)=O)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]4-carboxylic acid, and 3-aminopropionamide, the title compound was obtained in 87% purity by HPLC. MS(ESI+): m/z=437.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)[CH3:9].Cl[C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=1.O>C(#N)C>[CH2:8]([O:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[O:13][C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][N:26]=2)[CH2:15]1)[CH3:9]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CCOc1ccccc1O[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC[C@@H](Oc3ccccc3OCC)C2)nc1
Temperature: 90 °C
Yield: 60.9 %

Procedure:
Triethylamine (8.1 mL, 80 mmol) was added to a stirred solution of (R)-3-(2-ethoxy-phenoxy)-piperidine (10 g, 39 mmol) and ethyl 6-chloronicotinate (7.2 ml, 39 mmol) in acetonitrile (100 mL) at 0° C. The reaction mixture was heated at 90° C. for 16 h. The mixture was cooled to ambient temperature, water (150 mL) was added, and the mixture was extracted with ethyl acetate (3×200 mL). The combined organic layers were washed sequentially with water (100 mL) and brine (100 mL), then were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (13% ethyl acetate-hexanes) to afford ethyl (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinate (8.8 g). MS (ES+) 371.0 (M+H).
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.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]>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]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCCCCCCCCN
Solvent: CCN(CC)CC
Product: NCCCCCCCCNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(8-aminooctyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 1,8-diaminooctane, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.CCN(CC)CC.Cl[C:34]([O:36][CH3:37])=[O:35].O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:34]([O:36][CH3:37])=[O:35])[C@@H:6]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 2.5 °C
Reaction time: 1.5 h
Yield: 6.4 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(2-aminoethoxy)(3-chlorophenyl)methyl)morpholine-4-carboxylate (1.62 g, 4.38 mmol) and DMAP (280 mg) in dry CH2Cl2 (15 mL), Et3N (1.33 g, 13.14 mmol) was added. The resulting mixture was cooled to 0-5° C. in an ice-water bath and a solution of methyl chloroformate (2.06 g, 21.9 mmol) in dry CH2Cl2 (5 mL) was added dropwise. The reaction mixture was stirred for 1-2 h at 0-5° C. Tlc showed the starting material had disappeared. Water (30 mL) was added and the aqueous layer was extracted with CH2Cl2 (3×10 mL). The combined organic layers were washed with 10% aq citric acid (2×10 mL) and brine, dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford the desired product (120 mg, 6%). 1H NMR (MeOD) 1.45 (s, 9H), 2.80-2.92 (m, 2H), 3.0 (m, 1H), 3.60 (s, 3H), 4.15 (m, 2H), 4.25 (d, 1H), 7.20-7.35 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:30]3[C:25](=[CH:26][C:27](F)=[CH:28][CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=[O:14])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:47][CH:46]=2)=CC=1)([O-])=O>CS(C)=O.O>[N:51]1([C:48]2[CH:47]=[CH:46][C:45]([NH:44][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[C:30]5[C:25](=[CH:26][C:27]([N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)=[CH:28][CH:29]=5)[N:24]=[CH:23][N:22]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:50][CH:49]=2)[CH2:52][CH2:53][O:54][CH2:55][CH2:56]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Reactant: CN1CCNCC1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CN1CCN(c2ccc3c(C4CCN(C(=O)Nc5ccc(N6CCOCC6)cc5)CC4)ncnc3c2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A mixture of 1-methylpiperazine (0.11 mmol) and 4-(7-fluoro-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.05 mmol), prepared as described in Example 65, in DMSO (1 mL) was stirred at 120° C. for 1 h. It was then diluted with water and extracted with DCM. The combined extracts were washed with water, brine, dried (anhydrous MgSO4), filtered and concentrated in vacuo. The crude product was then treated with 3M HCl/MeOH (2 mL) and stirred at rt for 2 h and then concentrated in vacuo. The crude residue was dissolved in a mixture of DCM:MeOH (1:1; 2 mL) and neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), as prepared by the method outlined in Example 66a, at rt overnight. It was then concentrated in vacuo and the crude product was dissolved in DCM and washed with water thrice, then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude product was then purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH, 90:9:1) to obtain 5.5 mg (21%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.04 (s, 1H), 7.98 (d, 1H), 7.36-7.18 (m, 4H), 6.88 (d, 2H), 6.32 (s, 1H), 4.25 (m, 2H), 3.89-3.83 (m, 4H), 3.69-3.55 (m, 1H), 3.53-3.43 (m, 4H), 3.19-3.04 (m, 6H), 2.66-2.58 (m, 4H), 2.39 (s, 3H), 2.20-1.90 (m, 4H). LC/MS (ESI): 516.1 (MH)+.
Reaction SMILES: C1(C[O:8][C:9]2[CH:19]=[CH:18][C:12]3[C:13](=[O:17])[CH:14]=[CH:15][O:16][C:11]=3[C:10]=2[CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)C=CC=CC=1.CO.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:19]=[CH:18][C:12]2[C:13](=[O:17])[CH2:14][CH2:15][O:16][C:11]=2[C:10]=1[CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1ccoc2c(C/C=C/c3ccccc3)c(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Yield: 228.9 %

Procedure:
A mixture of 6.1 g (16.6 mmol) of (E)-7-(phenylmethoxy)-8-(3-phenyl-2-propenyl)-4H-1-benzopyran-4-one from the preceding example, 1 g of 10% palladium on carbon, 100 mL of methanol, and 300 mL of ethyl acetate was stirred at room temperature, in an atmosphere of hydrogen until approximately one third of the theoretical volume of hydrogen gas was taken up. The catalyst was filtered with suction and the filtrate concentrated in vacuo. The residue was dissolved in 150 mL of methanol and 0.5 g of Raney nickel was added. The hydrogenation was continued with careful monitoring by TLC analysis. When the reduction was essentially complete, the catalyst was filtered with suction and the filtrate concentrated in vacuo. The solid residue (4.75 g) was combined with 6.4 g from another experiment (23.9 mmol scale) and chromatographed on silica gel. Elution with hexane-ethyl acetate mixtures afforded 10.73 g (93.9%) of the title compound as a colorless solid, mp 110°-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH2:31])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:32]([CH3:34])[CH3:33])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:32]([CH3:34])[CH3:33])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NS(=O)(=O)c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (68.9 mg, 035 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methyl-pyridin-4-yl)-methanone (100 mg, 0.32 mmol) in pyridine (2 mL). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo. The resulting residue was triturated with MeOH, filtered, and dried. Purification by flash column chromatography [ethyl acetate/hexanes 3:7—(20% NH4OH/MeOH)/ethyl acetate/hexanes 5:65:30] afforded the title compound as a yellow oil (94 mg, 62%). MS: 469.3 (MH+); HPLC Rf: 4.46 min. (HPLC method 4).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([N:18]4[CH2:23][CH2:22][C:21]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][C:19]4=[O:34])[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[C:35]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:35][N:4]1[CH:5]=[CH:6][C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3([N:18]4[CH2:23][CH2:22][C:21]([CH2:30][C:31]([CH3:33])=[CH2:32])([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[O:20][C:19]4=[O:34])[CH2:16][CH2:17]3)=[CH:11][CH:10]=2)=[CH:8][C:3]1=[O:2]
Reactant: O=C([O-])[O-]
Reactant: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccnc(OC)c4)cc3)CC2)C(=O)O1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: C=C(C)CC1(c2ccccc2)CCN(C2(c3ccc(-c4ccn(C)c(=O)c4)cc3)CC2)C(=O)O1
Temperature: 90 °C
Yield: 83.4 %

Procedure:
A mixture of 3-(1-(4-(2-methoxypyridin-4-yl)phenyl)cyclopropyl)-6-(2-methylallyl)-6-phenyl-1,3-oxazinan-2-one (26.5 mg, 0.058 mmol), K2CO3 (16 mg, 2 equiv), iodomethane (250 μL, excess) and acetonitrile (3 mL) was heated at 90° C. for 1.5 h in the microwave oven. LC-MS found the reaction was complete. The mixture was filtered, concentrated, acidified with 5% aq HCl and purified by prep HPLC to afford the title compound (22 mg, 83%). LC-MS Method 1 tR=1.68 min, m/z=455.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[N+:30]([C:33]1C=CC=C2[C:34]=1[CH:35]=CN2)([O-:32])=[O:31].CC[N:44]([CH:48]([CH3:50])C)[CH:45]([CH3:47])[CH3:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.O.CO>[N+:30]([C:33]1[CH:46]=[C:45]2[C:47]([CH2:50][CH2:48][N:44]2[C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])=[CH:35][CH:34]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ccc([N+](=O)[O-])cc21

Procedure:
150 mg (0.37 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid-hydrochloride, 60 mg (0.37 mmol) 4-nitroindole, 0.15 mL (0.87 mmol) DIPEA and 130 mg (0.41 mmol) TBTU in 1.8 mL DMF were stirred overnight at RT. Then the reaction mixture was diluted with water/MeOH, the precipitate formed was suction filtered and washed with plenty of water. The precipitate was dried.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1.[CH3:25][CH2:26][O:27]CC.C(Cl)(=O)C>O>[C:26]([NH:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:27])[CH3:25]
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCCC2
Reactant: CCOCC
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)Nc1sc2c(c1C(=O)c1ccccc1)CCCC2

Procedure:
To a mixture of 35 g of 2-amino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene, 35 g of pyridine and 1950 ml of anhydrous ether is added dropwise 35 g of acetyl chloride. Then the reaction mixture is stirred under reflux for 3 hours. After cooling, the reaction mixture is poured into water. The ether layer is separated and washed with water, and dried over sodium sulfate. The solvent is removed under reduced pressure to give an oily residure, which is crystallized from ether to give 2-acetylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene having a melting point of 116° - 119°C.
Reaction SMILES: [H-].[Na+].N[C:4]1[C:5]([Cl:21])=[CH:6][C:7]([Cl:20])=[C:8]([N:10]2[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]2)[CH:9]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.C[N:33](C)C=O>>[Cl:20][C:7]1[C:6]([NH2:33])=[C:5]([Cl:21])[C:4]([C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)=[CH:9][C:8]=1[N:10]1[C:14](=[O:15])[N:13]([CH:16]([F:18])[F:17])[C:12]([CH3:19])=[N:11]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)C=O
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: [H-]
Agent: [Na+]
Product: Cc1nn(-c2cc(-c3ccc([N+](=O)[O-])cc3)c(Cl)c(N)c2Cl)c(=O)n1C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) mixture of 0.085 gram (0.00355 mole) of sodium hydride in 10 mL of N,N-dimethylformamide was added 1.0 gram (0.00323 mole) of 1-(5-amino-2,4-dichlorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one. After stirring for a brief period of time, 0.455 gram (0.00323 mole) of 4-fluoronitrobenzene was added. The resultant mixture was allowed to warm to room temperature and was stirred for one hour. The reaction mixture was heated at 60° C. for three hours and an additional 0.455 gram of 4-fluoronitrobenzene was added. This mixture was heated at 50° C. for approximately 18 hours. After cooling to room temperature, the mixture was poured into ice water. The aqueous mixture was extracted with three portions of ethyl acetate. The extracts were combined and washed in succession with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution, water, and an aqueous sodium chloride solution. The washed organic phase was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure to yield a solid. This solid was purified by recrystallization from ethyl acetate and n-heptane to yield 0.25 gram of 1-[2,4-dichloro-5-(4-nitrophenyl)-aminophenyl]-4-difluoromethyl-4,5-dihydro -3-methyl-1,2,4-triazol-5(1H)-one, m.p. 249°-251° C. The mother liquor from the recrystallization process was evaporated under reduced presure leaving 1.0 gram of an orange oil. Analysis of this oil by thin layer chromatography indicated it contained a substantial amount of the desired product.