Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:17]=[C:16]([CH3:18])[N:15]([CH3:19])[N:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][N:15]1[C:16]([CH3:18])=[CH:17][C:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)=[N:14]1
Reactant: Cc1cc(C2CCN(C(=O)OC(C)(C)C)C2)nn1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C2CCNC2)nn1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.1 %

Procedure:
To a stirred solution of 3-(1,5-dimethyl-1H-pyrazol-3-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.19 mmol) in dry CH2Cl2 (1 mL) was added TFA (2 mL, 20% in CH2Cl2) at 0° C. The reaction mixture was stirred at room temperature for 3 h. TLC showed the disappearance of starting material. The reaction mixture was concentrated in vacuum to afford crude 1,5-dimethyl-3-pyrrolidin-3-yl-1H-pyrazole (33 mg, 91%), which was used for the next step without purified.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH:21][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=3)=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCc2ccccc2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21

Procedure:
8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Intermediate A, Step 7, 21 g, 65 mmol) and nicotinic acid (12 g, 97.7 mmol) were suspended in DMF (240 mL). Diisopropylethylamine (33.7 g, 260.4 mmol) and then PyBOP (51 g, 97.7 mmol) were added and the resulting mixture stirred with overhead stirring for 3 days at ambient temperature. At this time, the resultant precipitate was isolated by vacuum filtration. After repeated washing with EtOAc, the material was dried under vacuum with slight heating to yield the title compound (27.3 g, 98%): HPLC MS RT=1.09 min, MH+=481.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.32 (1H, s), 8.89 (1H, br m), 8.84 (1H, d), 7.89 (1H, br m), 7.82 (1H, d), 7.37 (1H, d), 7.27 (1H, d), 7.16 (6H, m), 5.18 (2H, s), 4.36 (2H, t), 4.04 (2H, t), 3.78 (3H, s).
Reaction SMILES: NC1C([N+]([O-])=O)=CC=C2C=1C=CC=N2.NC1C(N)=CC=C2C=1C=CC=N2.[Sn](Cl)Cl.[NH2:30][C:31]1[C:40]([NH:41][C:42]([CH3:44])=[O:43])=[CH:39][CH:38]=[C:37]2[C:32]=1[CH:33]=[CH:34][CH:35]=[N:36]2.C(OC(=O)C)(=O)C.[CH2:52]([S:58][CH:59]([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[C:60](O)=[O:61])[CH2:53][CH2:54][CH2:55][CH2:56][CH3:57]>N1C=CC=CC=1>[NH:41]([C:40]1[C:31]([NH:30][C:60](=[O:61])[CH:59]([S:58][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[C:32]2[C:37](=[CH:38][CH:39]=1)[N:36]=[CH:35][CH:34]=[CH:33]2)[C:42]([CH3:44])=[O:43]
Reactant: CCCCCCCCC(SCCCCCC)C(=O)O
Reactant: CC(=O)Nc1ccc2ncccc2c1N
Agent: Cl[Sn]Cl
Agent: Nc1c([N+](=O)[O-])ccc2ncccc12
Agent: Nc1ccc2ncccc2c1N
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCC(SCCCCCC)C(=O)Nc1c(NC(C)=O)ccc2ncccc12

Procedure:
Commercially available 5-amino-6-nitroquinoline was reduced to 5,6-diaminoquinoline using a procedure analogous to that described in Example 34, except tin (II) chloride was used in place of iron. 5,6-Diaminoquinoline was converted to 5-amino-6-acetaminoquinoline by reaction with acetic anhydride and pyridine. Using the procedure outlined in Example 25, 5-amino-6-acetaminoquinoline and 2-(hexylthio)decanoic acid were coupled to give the title compound. Mass spectrum m/e: 471.3 (M+).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:39])=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26](=[O:37])[NH:27][C:28]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[O:30][N:29]=2)[C:21]([CH3:38])=[CH:20]3)[N:13]=[CH:12][N:11]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:31]1[O:30][N:29]=[C:28]([NH:27][C:26]([N:22]2[C:23]3[C:19](=[C:18]([F:39])[C:17]([O:16][C:14]4[CH:15]=[C:10]([CH2:9][NH:7][CH3:6])[N:11]=[CH:12][N:13]=4)=[CH:25][CH:24]=3)[CH:20]=[C:21]2[CH3:38])=[O:37])[CH:32]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2n1C(=O)Nc1cc(C(C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(Oc2ccc3c(cc(C)n3C(=O)Nc3cc(C(C)(C)C)on3)c2F)ncn1

Procedure:
To a solution of {6-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.25 g, 0.452 mmol) in DCM (10 mL) is added TFA (1.5 mL). After 3 h the solvent is removed by rotary evaporation and the residue is diluted with DCM and water. Concentrated NH4OH is added to neutralize and the aqueous phase is extracted twice with DCM. The organic layers are washed with brine, dried over Na2SO4, and concentrated to give the title compound. MS (ESI) m/z 453.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J=1.01 Hz, 1H) 7.52 (d, J=8.59 Hz, 1H) 7.19 (s, 1H) 7.15 (dd, J=8.72, 7.71 Hz, 1H) 6.65 (s, 1H) 6.58 (s, 1H) 3.76 (s, 2H) 2.56 (s, 3H) 2.33 (s, 3H) 1.34 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:25]=[CH:24][C:23]4[NH:22][C:21]5[CH2:26][CH2:27][N:28]([CH2:30][C:31]6[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=6)[CH2:29][C:20]=5[C:19]=4[CH:18]=3)=[O:16])[CH2:10][CH2:9]2)[CH:2]=1.[H-].[Na+].[C:43](Cl)(=[O:45])[CH3:44]>CN(C=O)C>[C:43]([N:22]1[C:23]2[CH:24]=[CH:25][C:17]([C:15]([NH:14][CH:11]3[CH2:12][CH2:13][N:8]([CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH2:9][CH2:10]3)=[O:16])=[CH:18][C:19]=2[C:20]2[CH2:29][N:28]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)[CH2:27][CH2:26][C:21]1=2)(=[O:45])[CH3:44]
Reactant: O=C(NC1CCN(Cc2cccnc2)CC1)c1ccc2[nH]c3c(c2c1)CN(Cc1ccc(C(F)(F)F)cc1)CC3
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3cc(C(=O)NC4CCN(Cc5cccnc5)CC4)ccc31)CN(Cc1ccc(C(F)(F)F)cc1)CC2
Temperature: -25 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 11, 50 mg, 0.09 mmol) in DMF (1.0 mL), NaH (60%, 5 mg, 0.13 mmol) was added at room temperature. The resulting brown reaction mixture was allowed to stir for 20 min, cooled down to −25° C. and acetyl chloride (7 μL, 7.7 mg, 0.1 mmol) was added. The reaction mixture was then allowed to warm up to room temperature over 1 h and poured over ice-cold saturated NaHCO3 solution to give a brown precipitate which was collected and purified by reverse phase HPLC. The purified material was triturated with ethyl ether to provide 5-acetyl-N-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-2-(4-(trifluoromethyl)benzyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxamide (Compound 20) as its bistrifluoroacetate salt as a white solid (31%). 1H NMR (CD3OD, 300 MHz) 8.73 (d, J=1.7 Hz, 1H), 8.70 (dd, J=5.1, 1.5 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 8.07 (dt, J=7.4, 1.7 Hz, 1H), 7.97 (s, 1H), 7.87-7.79 (m, 5H), 7.61 (dd, J=8.0, 5.0 Hz, 1H), 4.69 (s, 2H), 4.53 (s, 2H), 4.45 (s, 2H), 4.26-4.14 (m, 1H), 3.77 (br s, 2H), 3.64-3.52 (m, 4H), 3.28-3.20 (m, 2H), 2.80 (s, 3H), 2.26 (d, J=14.4 Hz, 2H), 1.99 (br s, 2H) ppm; MS (ES) 590 (M+H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:16]3[N:15]=[CH:14][C:13]4[N:19]([CH3:30])[C:20](=[O:29])[N:21]([C:22]5[C:23]([CH3:28])=[N:24][N:25]([CH3:27])[CH:26]=5)[C:12]=4[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:42])[CH3:41]>ClCCl>[CH3:27][N:25]1[CH:26]=[C:22]([N:21]2[C:12]3[C:11]4[CH:10]=[C:9]([C:5]5[CH:4]=[C:3]([CH2:2][NH:1][C:40](=[O:42])[CH3:41])[CH:8]=[N:7][CH:6]=5)[CH:18]=[CH:17][C:16]=4[N:15]=[CH:14][C:13]=3[N:19]([CH3:30])[C:20]2=[O:29])[C:23]([CH3:28])=[N:24]1
Reactant: CC(=O)Cl
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(CN)c4)cc3c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1
Reaction time: 0.75 h

Procedure:
To a mixture of 8-(5-aminomethyl-pyridin-3-yl)-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 230, 0.053 mmol) and Hünig's base (0.014 ml) in dichloromethane (1 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.058 mmol). The RM was stirred for 45 min at it then evaporated to dryness. The residue was taken in MeOH and purified by preparative HPLC. The fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, evaporated and dried under vacuum to give the title compound as a white solid. (HPLC: tR 1.95 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.56-8.53 (m, 1H), 8.48-8.46 (m, 1H), 8.40 (t, 1H), 8.16-8.12 (m, 2H), 7.94-7.90 (m, 1H), 7.78-7.75 (m, 1H), 7.58-7.56 (m, 1H), 4.38-4.27 (m, 2H), 3.92 (s, 3H), 3.58 (s, 3H), 1.95 (s, 3H), 1.89 (s, 3H))
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].CO.[C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>COC(C)(C)C>[F:9][C:2]([F:1])([F:8])[C:3](=[O:5])[CH2:16][C:15]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccncc1
Agent: C[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reaction time: 22 h
Yield: 62.2 %

Procedure:
Ethyl trifluoroacetate (6.32 g) was dissolved in tert-butyl methyl ether (10 mL) and a 28% sodium methoxide-methanol solution (9.40 g) and a solution of 4-acetylpyridine (4.90 g) in tert-butyl methyl ether (20 mL) were added successively at room temperature. The mixture was stirred for 22 hr. A 10% a aqueous citric acid solution was added until the reaction solution became about pH 4, and the precipitate was collected by filtration, washed with water and dried to give 4-trifluoroacetoacetylpyridine (5.46 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28].C([O-])([O-])=O.[Cs+].[Cs+]>O.COCCOC.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>[CH3:24][O:25][C:26](=[O:46])[C:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=3)[N:5]=[C:6]([O:8][CH3:9])[N:7]=2)[CH:33]=[CH:32][C:31]=1[F:45])([CH3:29])[CH3:28]
Reactant: COc1nc(Cl)cc(NCCc2ccc(OC(F)(F)F)cc2)n1
Reactant: COC(=O)C(C)(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)C(C)(C)c1cc(-c2cc(NCCc3ccc(OC(F)(F)F)cc3)nc(OC)n2)ccc1F
Yield: 30.2 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-trifluoromethoxyphenyl)-ethyl]amine (1.6 g), 2-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-methyl-propionic acid methyl ester (0.63 g), Cs2CO3 (11.6 g) and tetrakis(triphenylphosphine)palladium (0) (33 mg) in water (8 mL) and DME (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted with EtOAc (2×200 mL). The combined extract is dried over sodium sulfate, filtered, evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 2-(2-fluoro-5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid methyl ester (300 mg). MS: 508 (M+H); 1H NMR (300 MHz, CD3OD) □7.8, (d, 1H, J=0.3 Hz); 7.7 (m, 1H); 7.4 (d, 2H, J=0.4 Hz); 7.2-7.3 (m, 4H); 6.6 (s, 1H); 4.2 (s, 3H); 4 (s, 3H); 3.9 (m, 2H); 3.05 (t, 2H); 1.65 (s, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.C=O.[BH3-][C:17]#N.[Na+]>C(O)(=O)C>[CH3:17][N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1
Reactant: [BH3-]C#N
Reactant: Brc1cncc(OC[C@@H]2CCN2)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC[C@H]1COc1cncc(Br)c1

Procedure:
A 480 mg sample of the free base of 3-(2-(S)-azetidinylmethoxy)-5-bromopyridine, from Example 67 above, was dissolved in 4 mL of acetic acid treated with 1 mL of 37% HCHO and 500 mg of NaBH3CN at 0° C. for 4 hr. The solvents were removed under reduced pressure. The residue was basified with NaHCO3 solution. The mixture was extracted with methylene chloride, the extract was dried over MgSO4, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with 200:1 and 100:1 chloroform:methanol to give 68 mg of the title compound. MS (DCI/NH3) m/e: 257/259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28 (d, J=1.9 Hz, 1H), 8.26 (d, J=2.6 Hz, 1H), 7.38 (dd, J=1.9, 2.6 Hz, 1H), 4.02 (d, J=6.3 Hz, 2H), 3.51-3.44 (m, 1H), 3.43-3.37 (m, 1H), 2.93-2.84 (m, 1H), 2.41 (s, 3H), 2.13-2.03 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>[Cu]>[CH:16]1[CH:15]=[C:14]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:13]([F:18])=[CH:12][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: Fc1ccccc1Br
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Product: Fc1ccc(Oc2ccccc2F)cc1
Reaction time: 0.17 h

Procedure:
4-Fluorophenol (1.12 g, 10 mmol) was heated to 50° C. KOH (0.56 g, 10 mmol) was added thereto, and the reaction mixture was stirred over 10 min. 2-Bromofluorobenzene (1.75 g, 10 mmol) and powdered copper (0.64 g) were added thereto. The reaction mixture was stirred at 110° C. over a further 2 hours. Unconverted 2-bromofluorobenzene was removed by means of vacuum distillation. The product was subsequently purified on a silica gel-packed column with n-hexane as the mobile phase. Yield: 1.0 g (4.8 mmol, 48%) of the product with a purity of 97.3%, determined by means GC. 1H NMR: δ 6.92-7.21 multiple peaks. 13C NMR: δ 158.0 (d, 1JC-F=341.2, C-4′), 154.8 (d, 1JC-F=348.5, C-2), 153.2 (d, 4JC-F=3.1, C-1′), 144.2 (d, 2JC-F=11.3, C-1), 124.7 (m, C-6, C-2′ and C-6′), 121.3 (d, 4JC-F=1.7, C-5), 118.9 (d, 3JC-F=8.3, C-4), 117.1 (d, 2JC-F=18.3, C-3), 116.2 (d, 2JC-F=23.8, C-3′ and C-5′).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].C(O)(=O)C.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=O)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[C:14]([O:13][C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][NH:1][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(O)CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(O)CNC[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 108.4 %

Procedure:
4.34 g of 1-amino-2-methylpropan-2-ol (48.68 mmol) are placed in 50 ml of MeOH. 2.79 ml of acetic acid (48.68 mmol) and then 4.72 ml of N-Boc-L-prolinal (24.34 mmol), diluted beforehand in 20 ml of MeOH, are successively added dropwise. The reaction mixture is stirred at room temperature for 30 minutes and 3.22 g of sodium cyanoborohydride (48.68 mmol) are then added portionwise. After stirring at room temperature for 18 hours, the medium is poured into 400 ml of saturated aqueous NaHCO3 solution. The aqueous phase is extracted with 3 times 150 ml of DCM. The organic phases are combined, washed with 200 ml of water, with 200 ml of brine, dried over MgSO4, filtered and evaporated. 7.19 g of (S)-2-[(2-hydroxy-2-methyl propylamino)methyl]pyrrolidine-1-carboxylic acid tert-butyl ester are obtained.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10](OC)=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1.O.[NH2:25][NH2:26]>CO>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH:25][NH2:26])=[O:11])=[N:8][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:6]1
Reactant: NN
Reactant: COC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2ccccn2)nn1Cc1ccccc1F
Temperature: 70 °C

Procedure:
To a solution of methyl 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carboxylate I-35 (115 mg, 0.368 mmol) in methanol (2 mL) was added hydrazine hydrate (72 μL, 1.5 mmol). The solution was heated to 70° C. for 3.5 h, at which point the solvent was removed in vacuo to give 1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazole-5-carbohydrazide C as a white solid. To the crude solid (17 mg, 0.054 mmol) suspended in ethyl acetate (600 μL) was added acetic formic anhydride (0.03 mL, taken from a 2:1 (molar ratio) of formic acid to acetic anhydride, allowed to age 2 h prior to addition). After stirring for 1.25 h, the solution was diluted with ethyl acetate (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were dried over MgSO4, filtered, and the solvent was removed in vacuo to give the crude intermediate D that was carried on without further purification. To the crude solid was added phosphoryl chloride (237 μl, 2.54 mmol) and the solution was heated to 60° C. for 6.5 h. The solution was diluted with ethyl acetate (75 mL) and saturated aqueous sodium bicarbonate (75 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The organics were washed with brine (50 mL), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. Purification by silica gel chromatography (20-95% ethyl acetate in hexanes) gave 2-(1-(2-fluorobenzyl)-3-(pyridin-2-yl)-1H-1,2,4-triazol-5-yl)-1,3,4-oxadiazole I-42 (7.5 mg, 0.023 mmol, 42% yield for three steps) as a white solid.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH:28]([CH2:29][C:30](O)=[O:31])[CH:24]([CH2:25][CH2:26][CH2:27]1)[CH2:23][CH2:22][CH2:21]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:24]12[CH:28]([CH2:29][C:30]([N:12]3[CH2:13][CH:14]4[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]4)[CH2:11]3)=[O:31])[CH:20]([CH2:27][CH2:26][CH2:25]1)[CH2:21][CH2:22][CH2:23]2
Reactant: O=C(O)CC1C2CCCC1CCC2
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1C3CCCC1CCC3)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 0.12 ml was added in a methylene chloride 10 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 100 mg and stirred at 0° C. for 30 min. 9-bicyclo[3.3.1]nonylacetic acid 97.0 mg and WSC 0.15 g were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 19 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (1S)-3-(bicyclo[3.3.1]nonan-9-yl)acetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 10 ml solution of lithium aluminum hydride 41 mg and refluxed under heating for 1 hour. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform:acetone=10:1-5:1) to obtain the product.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][NH:26][CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[C:23]1[CH2:27][N:26]([C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: Fc1ccc(Cl)c(C2=CC(c3ccccc3)NC2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CC(c2cc(F)ccc2Cl)=CC1c1ccccc1
Reaction time: 0.33 h

Procedure:
Triethylamine (149 μL, 1.07 mmol, 10.00 equiv) and pivaloyl chloride (26 μL, 0.214 mmol, 2.00 equiv) were added sequentially to a solution of 4-(2-chloro-5-fluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole (1-5, 0.107 mmol, 1 equiv) in dichloromethane (10 mL) at 23° C., and the resulting mixture was stirred for 20 minutes. The reaction mixture was concentrated and the residue purified by reverse-phase LC (H2O/CH3CN gradient w/0.1% TFA present) to provide 4-(2-chloro-5-fluorophenyl)-1-(2,2-dimethylpropanoyl)-2-phenyl-2,5-dihydro-1H-pyrrole (10-1) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.39 (dd, 1H, J=8.8, 5.2 Hz), 7.33 (m, 4H), 7.26 (m, 1H), 7.05 (dd, 1H, J=9.2, 3.1 Hz), 6.99 (m, 1H), 6.20 (m, 1H), 5.98 (m, 1H), 5.00 (m, 2H), 1.28 (s, 9H). LRMS m/z (M+H) 358.0 found, 358.1 required.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[N:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[S:22][C:12]=3[N:13]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccccc1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-4-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-benzylamino-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[N:18]([CH3:19])[N:17]=[C:16]([CH3:20])[C:15]=1[S:21]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:23]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(C)nn(C)c2Cl)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-chloro-1,3-dimethylpyrazole-4-sulfonyl chloride as described in the synthetic METHOD B to give a white solid (14.8 mg) with purity >90%. MS (pos) m/z 397.2, 381.2.