Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[O:29]([C:31]#[N:32])[K]>O.CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([C:31]([NH2:32])=[O:29])[CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(N3CCNCC3=O)cc2)nn1)c1ccc(Cl)s1
Reactant: N#CO[K]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)N1CCN(c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)C(=O)C1
Temperature: 25 °C

Procedure:
5-Chloro-N-((1-(4-(2-oxopiperazin-1-yl)phenyl)-1H-1,2,3-triazol-4-yl)methyl)thiophene-2-carboxamide (23 mg, 0.055 mmol, prepared as shown in Example 60) was dissolved in 2 mL water and 0.5 mL DMSO. To it was added KOCN (23 mg, 0.28 mmol). The mixture was stirred at RT over the weekend. The title compound was the major product in this reaction and was isolated using direct reverse phase prep HPLC. MS found for C19H18ClN7O3S (M+H)+ 460.1, 462.1 (Cl pattern).
Reaction SMILES: [O:1]([CH2:8][C@H:9]1[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([NH:19][CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[C:27]([OH:31])=[CH:28][CH:29]=[CH:30][C:22]=2[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[CH2:12]([N:19]([CH:20]1[CH2:26][CH2:25][CH2:24][C:23]2[C:27]([OH:31])=[CH:28][CH:29]=[CH:30][C:22]=2[CH2:21]1)[CH2:10][C@H:9]([OH:11])[CH2:8][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1cccc2c1CCCC(NCc1ccccc1)C2
Reactant: c1ccc(OC[C@@H]2CO2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Product: Oc1cccc2c1CCCC(N(Cc1ccccc1)C[C@H](O)COc1ccccc1)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.6 %

Procedure:
A suspension of (2S)-3-phenoxy-1,2-epoxypropane (300 mg) (IL FARMACO, 50 (10), 643 (1995)), N-benzyl-(1-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-yl)amine (535 mg), and ytterbium(III) trifluoromethanesulfonate (372 mg) in dichloromethane (15 ml) was stirred at room temperature for 3 days and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (dichloromethane-methanol) over silica gel (16 g) to afford (2S)-1-[N-benzyl-(6,7,8,9-tetrahydro-1-hydroxy-5H-benzocyclohepten-6-yl)amino]-3-phenoxy-2-propanol (747 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:26]([O:28][CH2:29][CH3:30])=[O:27]>ClCCl>[CH2:29]([O:28][C:26]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@@H:12]([CH3:17])[CH2:13]1)=[O:27])[CH3:30]
Reactant: C[C@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)OCc2ccccc2)[C@@H](C)C1

Procedure:
To a solution of 3.0 g (S)-2-Methyl-piperazine-1-carboxylic acid benzyl ester hydrotrifluoroacetate in 17 ml dichloromethane were added at 0° C. 7.1 ml triethylamine and 1.2 ml ethyl chloroformate. After 12 h the reaction mixture was diluted with dichloromethane and extracted with 0.1 M HCl and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and the crude product obtained after evaporation purified by chromatography on silica using heptane/ethyl acetate 2/1 as eluent. Yield: 3.5 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:17][S:8]([C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:12])(=[O:10])=[O:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1F
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A solution of 5-chloro-2-fluorobenzene-1-sulfonyl chloride (2.0 g) in tetrahydrofuran (30 ml) was added to a solution of tert-butylamine (9.15 ml) in tetrahydrofuran (70 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give N-tert-butyl-5-chloro-2-fluoro-benzenesulfonamide (2.2 g, 95% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][CH2:35][CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][CH2:35][CH2:36][N:37]([CH3:38])[C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: CC(C)(O)C(=O)O
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)C(C)(C)O
Yield: 39 %

Procedure:
The procedure described in Example 1 was repeated using 2-hydroxy-2-methylpropanoic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 39% yield; NMR spectrum (DMSO-d6) 1.20 (s, 6H), 3.34 (s, 3H), 3.89 (s, 2H), 4.43 (s, 2H), 5.27 (s, 1H), 5.31 (s, 2H), 7.18 (d, 1H), 7.24 (d, 1H), 7.32-7.40 (m, 2H), 7.53-7.57 (m, 1H), 7.58 (d, 1H), 7.70-7.76 (m, 1H), 7.86-7.91 (m, 2H), 8.43 (s, 1H), 8.59-8.61 (m, 1H), 9.75 (s, 1H); Mass spectrum MH+ 522.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][O:11][C:12]2[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N+:22]([CH3:25])([O-:24])=[O:23].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[F:5][C:6]1[CH:21]=[CH:20][C:9]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:25]/[N+:22]([O-:24])=[O:23])=[CH:16][N:17]=2)=[CH:8][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)nc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccc(OCc2ccc(F)cc2)nc1
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 98.3 %

Procedure:
To an acetic acid (20.0 mL) solution of 6-(4-fluoro-benzyloxy)-pyridine-3-carbaldehyde (2.23 g, 9.64 mmol) described in Manufacturing Example 58-1-2 were added nitromethane (2.94 g, 48.2 mmol) and ammonium acetate (1.49 g, 19.3 mmol) under nitrogen atmosphere, which was stirred for 2.5 hours at 105° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. This organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure to obtain the title compound (2.60 g) as a crude product.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:15][C:16]=1[NH2:17])=[O:10].CC(C)([O-])C.[K+].[CH3:34][O:35][CH2:36][C:37](=O)[CH2:38][C:39]([O:41][CH3:42])=[O:40].O>C1COCC1>[CH3:42][O:41][C:39]([C:38]1[C:37]([CH2:36][O:35][CH3:34])=[N:17][C:16]2[C:11]([C:9]=1[OH:10])=[CH:12][CH:13]=[C:14]([C:18]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][N:19]=1)[N:15]=2)=[O:40]
Reactant: Nc1nc(-c2ncccc2C(F)(F)F)ccc1C(=O)ON1C(=O)CCC1=O
Reactant: COCC(=O)CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (1-0.4 g, 27.3 mmol) in 50 mL dry THF is added in one portion to a mixture of potassium t-butoxide (7.36 g, 65.6 mmol) and methyl 4-methoxy-acetoacetate (8.77 g, 60.7 mmol) in dry THF (100 mL). The reaction is stirred overnight at room temperature. Water (30 mL) is added and the solution concentrated (˜30 mL). The resulting mixture is extracted with ether (2×50 mL). The aqueous portion is acidified with concentrated hydrochloric acid and extracted with CH2Cl2 (4×100 mL). The combined organic extracts are dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound as a light brown oil that solidifies upon standing.
Reaction SMILES: COC(=O)CC1CC2C(=CC(OCCNC(OC(C)(C)C)=O)=CC=2)NC1=O.[CH3:28][O:29][C:30](=[O:61])[CH2:31][CH:32]1[CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:42][CH2:43][CH2:44][NH:45]C(OC(C)(C)C)=O)=[CH:38][CH:39]=2)[N:34]([CH2:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:33]1=[O:60]>>[CH3:28][O:29][C:30](=[O:61])[CH2:31][CH:32]1[CH2:41][C:40]2[C:35](=[CH:36][C:37]([O:42][CH2:43][CH2:44][NH2:45])=[CH:38][CH:39]=2)[N:34]([CH2:53][C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:33]1=[O:60]
Reactant: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2N(Cc2ccccc2)C1=O
Agent: COC(=O)CC1Cc2ccc(OCCNC(=O)OC(C)(C)C)cc2NC1=O
Product: COC(=O)CC1Cc2ccc(OCCN)cc2N(Cc2ccccc2)C1=O

Procedure:
The title compound is prepared according to the procedure of Example 78 except that [7-(2-tert-butoxycarbonylamino-ethoxy)-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]-acetic acid methyl ester is replaced with [7-(2-tert-butoxycarbonylaminoethoxy)-1-benzyl-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl]acetic acid methyl ester.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.Cl>C1COCC1>[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccncc2)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of (R)-{2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-2-oxo-1-pyridin-4-ylmethyl-ethyl}-carbamic acid tert-butyl ester (7.96 g.; 18 mmol) from Example 6 in THF (60 mL) at 0° C. was added HCl (4M/Dioxane) (74 mL; 0.3 mol). The mixture was stirred at ambient temperature for 3 hours, and the solvent removed in vacuo. The residue was dissolved in water (70 mL), washed with ether (40 mL). The aqueous layer was rendered basic (pH 9–10) with saturated aqueous Na2CO3, and the product extracted into dichloromethane (3×60 mL). The combined dichloromethane layers were washed with brine, dried over MgSO4, filtered, and the solvent removed in vacuo to afford the free base of the title compound as a clear oil (6.12 g., 100%). An analytical sample was prepared by treatment with ethereal HCl to yield the hydrochloride salt as an off-white crystalline solid, m.p. >175–177° C.; MS (+) ESI, [M+H]+ @ m/z 341; 1H NMR, 400 MHz, DMSO-d6. Analysis for C19H24N4O2.1.1HCl.0.5H2O Calculated: C, 58.58; H, 6.75; N, 14.38 Found: C, 58.64; H, 6.46; N, 14.25.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:20][O:21][C:22](Cl)=[O:23]>ClCCl>[CH3:4][C:2]([N:5]([CH2:6][CH:7]([OH:12])[C:8]([Cl:11])([Cl:10])[Cl:9])[C:22](=[O:23])[O:21][CH3:20])([CH3:1])[CH3:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)NCC(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N(CC(O)C(Cl)(Cl)Cl)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
To a stirred solution of 5 grams of 3-(1,1-dimethylethylamino)-1,1,1-trichloro-2-propanol and 2.15 grams of triethylamine in 50 grams of dichloromethane, cooled to -60° C., 2.01 grams of methylchloroformate was added dropwise during 5 minutes. After allowing the reaction mixture to warm to ambient temperature during 1 hour, the mixture was stirred for 3 hours. The reaction mixture was evaporated under a reduced pressure of 100 mm. Hg to 5.6 grams of an oil which was crystallized from 50 grams of hexane to yield 5.2 grams of white methyl (1,1-dimethylethyl)-(3,3,3-trichloro-2-hydroxypropyl)carbamate melting 100°-101° C.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][CH2:22][O:23][CH:24]([C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:25]([OH:27])=O.[C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])(=[O:38])[NH:36][NH2:37]>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[Cl:20][CH2:21][CH2:22][O:23][CH:24]([C:28]1[CH:29]=[N:30][C:31]([Cl:34])=[CH:32][CH:33]=1)[C:25]([NH:37][NH:36][C:35]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:27]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)C(OCCCl)c1ccc(Cl)nc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)C(OCCCl)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
HOBT (681 mg), IPEA (1.98 mL) and EDC (966 mg) were sequentially added to a solution of (2-chloroethoxy)-(6-chloropyridin-3-yl)acetic acid (630 mg) and tert-butyl carbazate (400 mg) in DMF (15 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent solvent: heptane:ethyl acetate=1:2) to obtain 666 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: Nc1nc(C2CCCCC2)[nH]c(=O)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Nc1nc(C2CCCCC2)[nH]c(=O)c1N
Yield: 81.1 %

Procedure:
To water (50 ml.), stirred at 70° C, were added in alternate portions 4-amino-2-cyclohexyl-5-nitrosopyrimid-6-one (25 g.) and sodium dithionite until the blue colour was discharged. The pale yellow solid was filtered off and washed with water to give 4,5-diamino-2-cyclohexylpyrimid-6-one (19 g.), m.p. 232-238° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[F:27][CH:28]([F:38])[C:29]1[NH:33][C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[F:38][CH:28]([F:27])[C:29]1[N:30]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=4)[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(CN2C[C@@H]3COCCN3c3nc(-n4c(C(F)F)nc5ccccc54)ncc32)cc1
Temperature: 130 °C
Yield: 21.4 %

Procedure:
A mixture of (R)-2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x10 50 mg, 0.127 mmol), 2-(difluoromethyl)-1H-benzo[d]imidazole (21.29 mg, 0.127 mmol), cesium carbonate (61.9 mg, 0.190 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.64 mg, 5.06 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (4.83 mg, 10.13 μmol) in DMF 253 μL was heated to 130° C. in a microwave for 40 minutes. Additional tris(dibenzylideneacetone)dipalladium(0) (4.64 mg, 5.06 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (4.83 mg, 10.13 μmol) were added, and the reaction mixture was heated to 130° C. in a microwave for 1 hour. EtOAc and water were added and the mixture was filtered through Celite and extracted with EtOAc (2×). The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2—NH2, 30-100% EtOAc/hexane gradient) to afford the title compound as a yellow solid (14.3 mg, 21.4%). 1H NMR (400 MHz, CDCl3) δ 3.08 (s, 3 H), 3.19-3.38 (m, 4 H), 3.68 (td, J=12.00, 2.78 Hz, 1 H), 3.83-3.92 (m, 1 H), 3.94-4.02 (m, 1 H), 4.11-4.20 (m, 1 H), 4.44-4.63 (m, 3 H), 7.36-7.75 (m, 6 H), 7.93-8.01 (m, 3 H), 8.17-8.23 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C25H24F2N6O3S, 527.16; found 527.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[N:11]1([C:17]([S:19][CH3:20])=[S:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:14]1[CH2:15][CH2:16][N:11]([C:17]([S:19][CH3:20])=[S:18])[CH2:12][CH2:13]1
Reactant: COc1ccccc1CCl
Reactant: CSC(=S)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1CN1CCN(C(=S)SC)CC1
Yield: 44.7 %

Procedure:
In a nitrogen atmosphere, 2.28 g (14.5 mmol.) of 2-methoxybenzyl chloride, 2.69 g (14.5 mmol., purity 94.8%) of methyl 1-piperazinecarbodithioate, 1.53 g (14.5 mmol.) of anhydrous sodium carbonate and 15 ml of ethanol were mixed and refluxed under heating for 18 hours. Insolubles were removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. To the residue were added 15 ml of dichloromethane and 15 ml of water. The organic solvent portion was taken out, washed with 17 ml of 1-N hydrochloric acid and 20 ml of 1-N aqueous sodium hydroxide solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by column chromatography to give 1.92 g of methyl 4-(2-methoxybenzyl)-1-piperazinecarbodithioate, yield 44.7%.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1Cl.[CH3:20][NH2:21].O>CS(C)=O>[Cl:1][C:2]1[C:3](=[O:19])[N:4]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:5]=[CH:6][C:7]=1[NH:21][CH3:20]
Reactant: CC1(C)CC(n2ncc(Cl)c(Cl)c2=O)CC(C)(C)C1
Reactant: CN
Solvent: CS(C)=O
Solvent: O
Product: CNc1cnn(C2CC(C)(C)CC(C)(C)C2)c(=O)c1Cl
Temperature: 100 °C
Yield: 34.1 %

Procedure:
4,5-Dichloro-2-(3,3,5,5-tetramethylcyclohexyl)pyridazin-3-one (0.3 g, 1.475 mmoles) was dissolved in DMSO (20 mL) and a 40% aqueous solution of methylamine (0.6 mL, 1.7 mmoles) was added with stirring. Heated at 100° C. overnight. Allowed to cool and then poured into water. A solid precipitated out and was filtered off. Purified using a silica cartridge eluted with ethyl acetate:isohexane (3:7) to give the product as a cream solid (150 mg). 1H NMR (300 MHz CDCl3) 7.65 (s, 1H), 5.35 (m, 1H), 4.7 (brs, 1H), 3.05 (d, 3H, J=5 Hz), 1.55 (m, 4H), 1.3 (m, 1H), 1.15 (m, 1H), 1.15 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.[H-].[Na+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[C:18]1([S:24]([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:10]=3[C:2]([I:1])=[CH:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCOc1ncnc2[nH]cc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ncnc2c1c(I)cn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85.2 %

Procedure:
To 5-iodo-4-(2-methoxy-ethoxy)-7H-pyrrolo[2,3-d]pyrimidine (25, 3.67 g, 11.5 mmol) in 60.0 mL of tetrahydrofuran under an atmosphere of nitrogen, sodium hydride (506.0 mg, 12.65 mmol) is added. The reaction is stirred at room temperature for 20 minutes, then benzenesulfonyl chloride (26, 1.614 mL, 12.65 mmol) is added. The reaction is stirred at room temperature for 30 minutes, then poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (27, 4.50 g). MS (ESI) [M+H+]+=460.0.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CO[C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]2[C:21]([CH3:27])=[N:22][N:23]([CH3:26])[C:24]=2[CH3:25])[CH:13]=1.CN(C[N:33]1[C:37]2=[N:38][C:39]([N:42]3[CH2:47][CH2:46][CH:45]([N:48]([CH3:50])[CH3:49])[CH2:44][CH2:43]3)=[CH:40][CH:41]=[C:36]2[N:35]=[CH:34]1)C>>[CH3:49][N:48]([CH3:50])[CH:45]1[CH2:46][CH2:47][N:42]([C:39]2[N:38]=[C:37]3[NH:33][C:34]([C:11]([C:12]4[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([C:20]5[C:21]([CH3:27])=[N:22][N:23]([CH3:26])[C:24]=5[CH3:25])[CH:13]=4)=[O:28])=[N:35][C:36]3=[CH:41][CH:40]=2)[CH2:43][CH2:44]1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Reactant: COC(=O)c1ccc(C#N)c(-c2c(C)nn(C)c2C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1nn(C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)nc3[nH]2)ccc1C#N

Procedure:
Following General procedure P (LDA metallation, ketone formation and in situ deprotection) using 4-cyano-3-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzoic acid methyl ester and [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine to give 4-[5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzonitrile. (84%). HRMS m/z 483.2620 (M+H)+.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][C@@H:25]([CH:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])[C:24]1=[O:49])[CH2:21][CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:42][C:38]1[CH:37]=[C:36]([C@@H:27]2[C@@H:28]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][OH:18])[C:24](=[O:49])[C@H:25]([CH:43]([CH3:48])[C:44]([O:46][CH3:47])=[O:45])[CH2:26]2)[CH:41]=[CH:40][CH:39]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC[C@@H](CO)N1C(=O)[C@H](C(C)C(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)propanoate (285 mg, 0.398 mmol) (the less polar isomer from step D) in THF (1988 μL) was added TBAF (1.0M in THF) (1590 μL, 1.590 mmol). The mixture was stirred at room temperature for 16 h. The mixture was quenched with 1 M HCl and diluted with EtOAc. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (11 g VersaPak I-style, Spherical, Supelco, Bellenfonte, Pa.; eluent: 50 to 75% MtBE in hexanes) to give the title compound.