Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:37]>CO.CCOCC>[ClH:37].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reaction time: 18 h
Yield: 85 %

Procedure:
tert-Butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (12.0 g, 24.7 mmol) was dissolved in MeOH (100 mL), and 2 N HCl in Et2O (300 mL) was added. The reaction was allowed to proceed for 18 h. The mixture was concentrated, and the residue was partitioned between CH2Cl2 and sat. Na2CO3 solution. The organic phase was removed, and the aqueous phase was back extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness providing the free base of the title compound (8.1 g, 85%) as a yellow solid. A portion of the free base was converted to the HCl salt for biological testing. Free base: 1H NMR (500 MHz, CDCl3) δ 7.47-7.34 (m, 6H), 7.32-7.28 (m, 2H), 6.98 (d, J=7.1 Hz, 1H), 6.07 (d, J=2.6 Hz, 1H), 6.04 (dd, J=7.5, 2.6 Hz, 1H), 5.05 (s, 2H), 4.15 (s, 2H), 3.61 (s, 3H), 3.34 (br s, 2H), 2.78 (br s, 2H). HCl salt: melting point (mp) 296-302° C.; 1H NMR (500 MHz, CD3OD) δ 7.61-7.57 (2×d, 2H), 7.47-7.46 (m, 3H), 7.43-7.40 (m, 2H), 7.37-7.34 (m, 1H), 7.05 (dd, J=8.3, 1.7 Hz, 1H), 6.33 (dd, J=7.5, 2.7 Hz, 1H), 6.16 (d, J=2.6 Hz, 1H), 5.19 (s, 2H), 4.57 (s, 2H), 3.73 (s, 3H), 3.67 (t, J=6.2 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 386 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=13.6 min.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8](Cl)=[O:9])[CH2:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[NH:20][CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)=[O:14].CCOC(C)=O>CN(C1C=CN=CC=1)C.ClC(Cl)C>[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([C:31]#[C:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:18][C:19]=1[N:20]([CH:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][CH2:22]1)[C:8]([CH:5]1[CH2:6][CH2:7][C:2]([CH3:1])=[CH:3][CH2:4]1)=[O:9])=[O:14]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC2(CC1)OCCO2
Reactant: CC1=CC[C@@H](C(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid chloride (1.8 mmol), 5-(3,3-dimethyl-but-1-ynyl)-3-(1,4-dioxa-spiro[4.5]dec-8-ylamino)-thiophene-2-carboxylic acid methyl ester (336 mg, 0.89 mmol) and DMAP (217 mg, 1.8 mmol) were dissolved in dichloroethane (2.2 mL), sealed with a cap and heated to 80° C. After 2 h, the temperature was increased to 90° C., and the solution was stirred 16 h. The reaction mixture was further heated to 100° C., stirred 24 h and partitioned between water and ethyl acetate:hexanes (1:1). The layers were separated and the aqueous layer was extracted again with ethyl acetate:hexanes (1:1). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Flash chromatography (5% EtOAc:hexanes 5 min then 5-40% EtOAc:hexanes, 20 min, 24 g column) afforded 250 mg (56% yield of the desired 5-(3,3-dimethyl-but-1-ynyl)-3-[(1,4-dioxa-spiro[4.5]dec-8-yl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([CH2:34][CH3:35])[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:37]=[CH:36][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([CH2:34][CH3:35])[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:16])([CH3:15])[CH3:17]
Reactant: CCN(CCNCc1ccc(C(C)(C)C)cc1)c1cccc(C)c1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCN(CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cc(Cl)cc2cc[nH]c12)c1cccc(C)c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
97 mg (0.50 mol) of 5-chloro-1H-indole-7-carboxylic acid, 162 mg (0.5 mmol) of N′-(4-tert-butyl-benzyl)-N-ethyl-N-m-tolyl-ethane-1,2-diamine and 108 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 150 mg (60%) product as a colorless oil. MS (ISP) 502.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9]Br)[CH:3]=1.[CH3:11][C:12]1[N:17]=[C:16]([SH:18])[N:15]=[C:14]([OH:19])[CH:13]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][S:18][C:16]2[N:15]=[C:14]([OH:19])[CH:13]=[C:12]([CH3:11])[N:17]=2)[CH:3]=1
Reactant: Clc1ccc(Br)cc1CBr
Reactant: Cc1cc(O)nc(S)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2cc(Br)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A mixture of 4-bromo-2-(bromomethyl)-1-chlorobenzene (4.76 g. 16.7 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (1.83 g, 12.9 mmol), and triethylamine (5 mL, 36.0 mmol) in absolute ethanol (200 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness. The solid residue was treated with water (500 mL). The solid product was recovered by filtration, washed with water (2×50 mL), diethyl ether (3×50 mL), and hexanes (3×50 mL), and then dried in vacuo, affording the title compound (3.23 g, 56% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.00 (s (br), 1H), 7.41 (d, 1H, J=8.4 Hz), 7.53 (dd, 1H, J=2.3 Hz, 8.4 Hz), 7.86 (d, 1H, J=2.0 Hz); M+347.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Reactant: O=C(Cl)c1ccnc(Cl)c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccnc(Cl)c2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
Using an analogous procedure to that described in Example 2, except that the reaction mixture was heated to 80° C. for 5 hours, 2-chloropyridine-4-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-2-morpholinopyridine-4-carboxamide to give the title compound in 95% yield; NMR Spectrum: (DMSOd6) 3.53 (m, 4H), 3.75 (m, 4H), 7.11 (d, 1H), 7.27 (s, 1H), 7.56 (d, 1H), 7.73 (d, I1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.06 (s, 1H), 8.26 (d, 1H), 8.64 (d, 1H), 10.53 (m, 2H); Mass Spectrum: M+H+ 472.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]([Cl:28])([Cl:27])[CH2:25]O.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:23][C:24]([Cl:28])([Cl:27])[CH2:25][O:14][C:13](=[O:15])[CH:12]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: OCC(Cl)(Cl)Cl
Reactant: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)O)C(=O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C1CC(C(NC(=O)OCc2ccccc2)C(=O)OCC(Cl)(Cl)Cl)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In 30 ml of tetrahydrofuran were dissolved 1.53 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine and 1 ml of 2,2,2-trichloroethanol and under cooling at 0°-5° C., 0.8 ml of pyridine was added. Then, 1.2 g of dicyclohexylcarbodiimide was added and the mixture was stirred at the same temperature as above for 2 hours and at room temperature for 18 hours. The precipitated dicyclohexylurea separating out was filtered off and the filtrate was concentrated under reduced pressure. The residue was added to a mixture of 2 N hydrochloric acid and ethyl acetates and the ethyl acetate layer was separated, washed with 2 N hydrochloric acid, dried over sodium sulfate and concentrated under reduced pressure. The concentrate was chromatographed on a silica gel column and eluted with toluene-ethyl acetate (3:1). The eluate was concentrated under reduced pressure and the residue was crystallized from ethyl ether-petroleum ether. Yield 0.7 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:33])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(CO)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCl)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 62.8 %

Procedure:
To a solution of 4-methoxy-3-nitrobenzyl alcohol (4.9 g, 24.4 mmol) in 150 mL of dichloromethane was added triphenylphosphine (4.2 g, 31.7 mmol). The reaction was cooled to 0° C. and N-chlorosuccinimide (8.3 g, 31.7 mmol) was added. The reaction was warmed to room temperature and then heated gently to 50° C. for 2 h. The reaction was poured into aqueous sodium carbonate solution and the aqueous layer was extracted with dichloromethane and then ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent to give 4-methoxy-3-nitrobenzyl chloride (3.09 g, 63%). 1H NMR (400 MHz, CDCl3) δ ppm 7.98 (d, J=2.4 Hz, 1H), 7.73 (d, J=8.8, 2.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 4.78 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:24])=[O:23])=[CH:17]2.[S:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH2:42].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16]([S:22]([NH:42][C:38]1[S:37][CH:41]=[CH:40][N:39]=1)(=[O:24])=[O:23])=[CH:17]2
Reactant: Nc1nccs1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3Cl)cccc2c1
Temperature: -78 °C
Yield: 66 %

Procedure:
To a vial charged with perfluorophenyl 5-(2-chloro-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (0.200 g, 0.362 mmol) and THF (1 mL), was added thiazol-2-amine (0.040 g, 0.398 mmol) as a solution in THF (2 mL). The solution was cooled to −78° C., and a THF solution of lithium bis(trimethylsilyl)amide (0.724 ml, 0.724 mmol, 1M) was added dropwise by syringe. The solution was maintained at −78° C. for 5 min and then allowed to warm to rt. The solution was concentrated and the crude residue was absorbed onto a 5 g plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 5% to 90% EtOAc in hexane, to provide 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (0.112 g, 0.239 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 6.83 (d, J=4.59 Hz, 1H) 7.24 (d, J=4.59 Hz, 1H) 7.47 (d, J=8.98 Hz, 1H) 7.60 (d, J=7.16 Hz, 1H) 7.66-7.83 (m, 3H) 7.88 (d, J=8.23 Hz, 1H) 8.09 (s, 1H) 8.29 (d, J=8.33 Hz, 1H) 8.56 (d, J=1.71 Hz, 1H) 12.80 (br. s., 1H); m/z (ESI, +ve ion) 468.9 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].[CH3:49][C:50]1[CH:51]=[CH:52][C:53]([Sn](CCCC)(CCCC)CCCC)=[N:54][CH:55]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C@H:8]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C@@H:9]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:10][C@@H:11]([NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:53]2[CH:52]=[CH:51][C:50]([CH3:49])=[CH:55][N:54]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C[C@@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Yield: 73.5 %

Procedure:
A solution containing the product from Example 92D (0.50 g, 0.703 mmol) in DMF (7 mL) was treated with LiCl (0.30 g, 7.08 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol), and the product from Example 74A (0.805 g, 2.11 mmol), heated at 100° C. for 16 hours, cooled, filtered through celite®, and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in chloroform to give the title compound (0.374 g, 74% yield).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:28]3[CH2:29][CH2:30][CH2:31][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: CN1CCCNCC1
Product: CN1CCCN(c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cn2)CC1

Procedure:
50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with 1-methyl-1,4-diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinamide.
Reaction SMILES: Cl[CH2:2][C@H:3]([OH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O:11]1[C:16]2[CH:17]=[CH:18][C:19]([N:21]=[C:22]=[O:23])=[CH:20][C:15]=2[O:14][CH2:13][CH2:12]1>C1C=CC=CC=1>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][C@H:3]1[O:10][C:22](=[O:23])[N:21]([C:19]2[CH:18]=[CH:17][C:16]3[O:11][CH2:12][CH2:13][O:14][C:15]=3[CH:20]=2)[CH2:2]1)[CH3:9]
Reactant: O=C=Nc1ccc2c(c1)OCCO2
Reactant: CCOC(=O)C[C@@H](O)CCl
Solvent: c1ccccc1
Product: CCOC(=O)C[C@@H]1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Yield: 90 %

Procedure:
A solution of ethyl (R)-4-chloro-3-hydroxybutyrate (5.0 g, 30 mmol) and 2,3-dihydro-1,4-benzodioxin-6-yl isocyanate (5.3 g, 30 mmol) in benzene (150 ml) was stirred at 80° C. for 48 h. The reaction mixture was concentrated in vacuo, taken up in EA and washed twice with brine. The org. layer was dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (hept/EA 9:1 to 1:1) to give the desired carbamate (8.3 g, 81% yield) as a yellow oil. This intermediate was dissolved in DMF (40 ml) and treated with K2CO3 (3.3 g, 24 mmol). The heterogeneous mixture was stirred at rt for 20 h, water was added and the mixture extracted with EA. The org. layers were washed with water and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography on SiO2 (Hept/EA 2:1, 1:1) to give the desired oxazolidinone (0.96 g, 13% yield) as an orange solid.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:11][C@H:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=O)(C)(C)C.O.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(OCC)C>[C:20]1([CH3:30])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:8][C@H:9]1[CH2:11][CH2:21][CH2:20][C@H:10]1[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H]1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 180.9 %

Procedure:
To a mixture of tert-butyl rel-(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopropanecarboxylate (0.54 g) and diethyl ether (4.0 ml) was added a solution of p-toluene sulfonic acid monohydrate (0.40 g) in diethyl ether (16 ml) at room temperature, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to obtain tert-butyl rel-(1R,2S)-2-aminocyclopentanecarboxylate p-toluene sulfonate (0.68 g). Tert-butyl rel-(1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopropanecarboxylate (0.20 g) was obtained by using tert-butyl rel-(1R,2S)-2-aminocyclopropanecarboxylate p-toluene sulfonate (0.64 g) in the same method as for Production Process A1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].N[C:9](N)=[O:10]>O>[OH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][NH:7][C:9]1=[O:10]
Reactant: NC(N)=O
Reactant: NCCNCCO
Solvent: O
Product: O=C1NCCN1CCO
Temperature: 210 °C
Yield: 76.9 %

Procedure:
A mixture of N-(2-hydroxyethyl)ethylenediamine (31.2 g), urea (23.4 g) and water (3 ml) was heated at 130° C. for 3 hours and at 210° C. for 8 hours and then distilled directly from the reaction mixture to give 1-(2-hydroxyethyl)-2-imidazolidinone (30 g) as an oil [(b.p. 150°-160° C. (0.2 mm)] which solidified to give a solid (m.p. 50-51).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:4]
Reactant: NNC(N)=S
Reactant: O=C(CNC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CNC(=O)c1ccccc1)c1ccccc1
Yield: 109.6 %

Procedure:
Thiosemicarbazide (1.33 g, 14.6 mmol) was added to a solution of N-(2-oxo-2-phenyl-ethyl)-benzamide (3.5 g, 14.6 mmol), prepared in the previous step, in 53 ml of methanol plus 4 ml of 1N HCl plus 3.75 ml of water and the reaction stirred at room temperature overnight. The solvent was removed under reduced pressure to give 5.0 g of an off-white solid. Recrystallization of this solid from isopropyl alcohol gave the title compound (3.64 g, 80%) as a white solid, mp 171-172° C.
Reaction SMILES: [CH2:1]([C:8]1[C:13](Br)=[CH:12][N:11]=[C:10]([O:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][N:11]=[C:10]([O:15][CH2:16][C:17]2[O:18][CH:19]=[CH:20][CH:21]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: Brc1cnc(OCc2ccco2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@]1(C#Cc2cnc(OCc3ccco3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 4 h
Yield: 47.3 %

Procedure:
A mixture of 50.9 mg of 4-benzyl-2-(2-furylmethoxy)-5-bromopyrimidine, 26.8 mg of (3R)-3-ethynyl-3-quinuclidinol, 8.5 mg of tetrakis(triphenylphosphine)palladium(0), 0.3 mg of cuprous iodide, 61.5 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 90° C. for 4 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 29.0 mg of the target compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:41])[CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:42].C(OC(=O)C)C>>[ClH:42].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:27])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:28])[C:6]([C:29](=[O:41])[CH:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cn(C2CC2)c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)cc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Reaction time: 2 h
Yield: 97 %

Procedure:
5.74 g of the compound obtained from Example 17 was dissolved in 100 ml of 10% HCl-ethylacetate solution, and the solution was stirred for 2 hours. The resulting solid was filtered, and then dried to obtain 4.95 g of the object compound
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([NH2:6])[CH2:2]1.S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[O:1]1[CH2:5][CH2:4][CH:3]([NH:6][C:8]2[CH2:12][S:11][C:10](=[O:13])[N:9]=2)[CH2:2]1
Reactant: NC1CCOC1
Reactant: O=C1NC(=S)CS1
Solvent: CCO
Product: O=C1N=C(NC2CCOC2)CS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of tetrahydrofuran-3-amine (2.94 g) in ethanol (20 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3.0 g), and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration and washed with ethanol to give the title compound (2.41 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1.[CH3:24][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]([OH:10])[CH3:24])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[N:3]=1
Reactant: C[Mg]Br
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nc(Cl)c1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)nc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of 2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidine-5-carbaldehyde (797 mg, 2.14 mmol) in THF (10 mL) was added methyl magnesium bromide (3.0 M in diethyl ether, 6.4 mL, 19.3 mmol) at −78° C. under nitrogen atmosphere. The reaction mixture was warmed to room temperature gradually, and stirred overnight. The reaction mixture was poured into 20 mL of saturated aqueous NH4Cl at 0° C., and partitioned between EtOAc (30 mL×2) and brine (10 mL×2). The collected organic extracts were dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (EtOAc/Hexanes: 30/70) to afford 1-(2,4-dichloro-6-(2-(isopropylsulfonyl)phenylamino)pyrimidin-5-yl)ethanol. MS (ES+): 390.0 (MH+).