Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23](S(C)(=O)=O)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1COCC1>[CH2:1]([NH:8][C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:21]3[N:22]=[C:23]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:24]=[C:25]([CH3:26])[C:20]=3[CH:19]=[CH:18][C:17]2=[O:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCNCC2)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
The resin (A3), 0.0214 mmol) was suspended in THF (1 ml) and NEt3 (14 mg, 0.14 mmol). To this mixture was added piperazine (21 mg, 0.128 mmol) and shaking continued for 18 h. The resin was washed with THF (2×1 min), DMF (3×1 min, 60° C.) and with DCM (3×1 min) at rt.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][N:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:29][C:26]1[CH:25]=[N:24][C:23]([NH:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:28][CH:27]=1
Reactant: CN(C)CCNc1ccc(N)cn1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CN(C)CCNc1ccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)cn1
Yield: 66 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with N2-(2-(dimethylamino)ethyl)pyridine-2,5-diamine (270 mg, 1.5 mmol) to afford the desired product (300 mg, 66%) as a yellow solid: ESI MS m/z 454 [C22H24BrN5O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]3[CH:14]=[CH:13][CH:12]=[C:8]3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:21]I.Cl>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][N:7]3[CH:14]=[C:13]([CH3:21])[CH:12]=[C:8]3[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2Cn2cccc21
Reactant: CI
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc2n(c1)Cc1ccc(Cl)cc1NC2=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2.33 g of 8-chloro-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one in 50 mL of methylene chloride is added 5.33 g of aluminum trichloride in small aliquots over a 30 minute period. During this time the temperature of the reaction is maintained below 30°. To this reaction mixture 4 mL of methyl iodide is added, and the reaction is allowed to stir for 48 hours at room temperature. The reaction mixture is diluted with 24 mL of methanol and then poured into 150 mL of dilute hydrochloric acid. The methylene chloride layer is separated and washed with 200 mL of brine and saturated aqueous sodium bicarbonate. The methylene chloride extract is dried over anhydrous magnesium sulfate and evaporated to dryness to yield 8-chloro-2-methyl-10,11-dihydro-5-H-pyrrolo-[2,1-c][1,4]benzodiazepine-11-one, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:9])=[N:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:17][C:18]1[N:22]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=2)[N:21]=[CH:20][C:19]=1[C:33](Cl)=[O:34]>O1CCCC1>[Br:9][C:5]1[N:6]=[C:7]([CH3:8])[C:2]([NH:1][C:33]([C:19]2[CH:20]=[N:21][N:22]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=3)[C:18]=2[CH3:17])=[O:34])=[CH:3][CH:4]=1
Reactant: Cc1nc(Br)ccc1N
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Br)ccc1NC(=O)c1cnn(-c2ccc(C(F)(F)F)cn2)c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.6 %

Procedure:
To a solution of 5-amino-2-bromo-6-picoline (701 mg) and triethylamine (1.57 ml) in tetrahydrofuran (20 ml) was added 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid chloride (1.34 g) described in Reference Example 180 under ice-cooling, and stirred at room temperature for 1.5 hours. After completion of the reaction, the solvent was evaporated, and saturated sodium bicarbonate water was added thereto. The insoluble matter was collected by filtration, washed with water, and then dried in vacuo to give the titled compound as a pale yellow solid (1.66 g). MS (ESI) m/z: 440 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C@@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22].Cl>CO.O1CCOCC1>[NH2:25][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:22])[F:23])[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reaction time: 12 h
Yield: 109.2 %

Procedure:
To a solution of 1,1-dimethylethyl ((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)carbamate (3.2 g, 7.1 mmol) in MeOH (35 mL) at RT was added 4M HCl in dioxane (18 mL). After 12 h, the solution was concentrated affording the title compound (2.7 g, quant.) as the HCl salt: LCMS (ES) m/z 349 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:17]=[CH:16][C:11]3[NH:12][C:13](=[O:15])[S:14][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][NH2:28])=[CH:21][CH:20]=1.[BH4-].[Na+]>CC(O)C>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][NH:28][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:17]=[CH:16][C:11]4[NH:12][C:13](=[O:15])[S:14][C:10]=4[CH:9]=3)[CH2:4][CH2:3]2)=[CH:23][CH:24]=1
Reactant: O=C1CCC(c2ccc3[nH]c(=O)sc3c2)CC1
Reactant: NCCCc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(F)cc4)CC3)cc2s1
Reaction time: 4 h

Procedure:
To a solution of ketone 25 (2.3 g, 9.3 mmol) in 2-propanol (30 mL) was added 4 Å molecular sieves and 3-(4-fluorophenyl)-1-propylamine (1.76 g, 9.3 mmol). The reaction mixture was stirred for 4 hours. Sodium borohydride (0.49 g, 13.03 mmol) was added, and the reaction mixture was stirred overnight, quenched with MeOH, and concentrated under reduced pressure. Purification by flash chromatography (silica, 9.5:5:1 CH2Cl2:MeOH:NH4OH) gave 6-{trans-4-[3-(4-fluorophenyl)propylamino]cyclohexyl}-3H-benzthiazol-2-one (0.24 g, 7%): 1H NMR (500 MHz, DMSO-d6): δ 7.39 (s, 1H), 7.25-7.06 (m, 6H), 3.01 (m, 1H), 2.86 (t, J=8 Hz, 2H), 2.61 (t, J=8 Hz, 2H), 2.37 (m, 1H), 2.01 (m, 2H), 1.92-1.81 (m, 4H), 1.49-1.36 (m, 4H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:28]1([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([CH:41]=[CH:42][CH:43]=[O:44])[CH2:37][CH2:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1.C1CCCCC1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[CH:12]=[C:11]2[C:42](=[CH:41][CH:38]2[CH2:37][CH2:36][N:35]([CH2:34][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:40][CH2:39]2)[CH2:43][OH:44])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CC=CC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc2ccn(S(=O)(=O)c3ccccc3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc2cc(C(=CC3CCN(Cc4ccccc4)CC3)CO)n(S(=O)(=O)c3ccccc3)c2c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
A solution of N-phenylsulfonyl-6-methyl indole (1.18 g, 4.34 mmol) in 30 ml of dry THF was cooled to −78° C. and treated with 3.5 ml (5.2 mmol) of 1.5 M lithium diisopropylamide in cyclohexane at −78° C. After stirring at −78° C. for 1 hour, a solution of 3-[1-(phenylmethyl)-4-piperidinyl]-2-propenal (1.0 g, 4.36 mmol) in 5 ml of dry THF was added at −78° C. and stirred at that temperature for 40 minutes. The mixture was quenched with water and extracted with chloroform. The organic layer was dried and concentrated to give 2.23 g of an orange oil. The oil was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 1.0 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.[CH3:20][O:21][N:22]([CH3:26])[C:23](Cl)=[O:24]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH:16][C:23]([N:22]([O:21][CH3:20])[CH3:26])=[O:24])=[CH:14][CH:13]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CON(C)C(=O)Cl
Reactant: CC1(C)Cc2cc(Oc3ccc(N)cc3)ccc2O1
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(Oc2ccc3c(c2)CC(C)(C)O3)cc1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
6.5 g of 4-(2,3-dihydro-2,2-dimethyl-5-benzofuranyloxy)aniline was dissolved in 30 ml of pyridine, and 3.8 g of N-methoxy-N-methylcarbamoyl chloride was gradually dropwise added thereto over a period of 30 minutes under cooling with ice. Stirring was continued for 1.5 hours, and then pyridine was distilled off under reduced pressure. The residual oily substance was dissolved in 100 ml of toluene, and washed sequentially with water, a dilute hydrochloric acid aqueous solution and a saturated sodium chloride aqueous solution. Then, toluene was distilled off. The residue was purified by silica gel column chromatography by using a solvent mixture of ethyl acetate/n-hexane=1/3 as the developer, to obtain 7.5 g of compound No. 19 as identified in Table 1.
Reaction SMILES: C([Li:5])CCC.[CH3:6][N:7]([CH3:15])[C:8]1[C:9]([CH3:14])=[CH:10][CH:11]=[CH:12][CH:13]=1>CCCCCC.C(OCC)C>[CH3:6][N:7]([CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][Li:5]
Reactant: [Li]CCCC
Reactant: Cc1ccccc1N(C)C
Solvent: CCOCC
Solvent: CCCCCC
Product: [Li]Cc1ccccc1N(C)C

Procedure:
To a mixture of 23 ml of a 1.6 M solution of butyllithium in hexane and 10 ml of ethyl ether was added 5.0 g of N,N-dimethyl-o-toluidine with stirring. The mixture gradually became yellow and overnight a pale yellow solid was deposited. It was separated by filtration and dried, to give 2.0 g of 2-dimethylaminobenzyllithium.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[NH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17]>CC#N>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:14][CH2:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NC[C@H](O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4,6-dichloropyrimidine (50 g, 0.34 mol, 1.0 equiv) in CH3CN (1.2 L), was added NaHCO3 (34 g, 0.40 mol, 1.2 equiv) and (R)-(−)-2-amino-1-phenyl-ethanol (48.3 g, 0.35 mol, 1.05 equiv) sequentially. The reaction mixture was stirred at reflux temperature under N2 for 3 hours then cooled to rt. HPLC analysis of the crude reaction mixture indicated that the reaction was complete, to afford the intermediate (1R)-2-[(6-chloropyrimidin-4-yl)amino]-1-phenylethanol. In the same flask, without purification or work-up, was added a solution of K3PO4 (85 g, 0.40 mol, 1.2 equiv) in H2O (750 mL), 3-chloro-4-(trifluoromethyl)phenylboronic acid (79.4 g, 0.35 mol, 1.05 equiv), Pd(dppf)Cl2. CH2Cl2 (2.4 g, 2.9 mmol, 0.009 equiv) and Pd(OAc)2 (68 mg, 0.29 mmol, 0.0009 equiv) sequentially under N2 at rt. The reaction solution was degassed with N2 (3×) and was stirred at reflux temperature for 16 hours then cooled to rt. The layers were separated and the CH3CN phase was dried (MgSO4) and filtered. The filtrate solution was stirred with Si-Thiol (8.8 g, 1.5 mmol/g loading, 4 equiv of Pd added) at rt for 1 hour. Si-Thiol is commercially available through SiliCycle (230-400 mesh, 40-63 μm). The Si-Thiol was removed by filtration and washed with EtOAc. The organics were combined and concentrated under reduced pressure. The crude residue was recrystallized from hot EtOH (−250 mL) with stirring to afford the title compound (83 g). Further concentration of the mother liquor followed by a second recrystallization from hot EtOH with stirring provided an additional crop of the title compound (23 g). The combined recrystallized yield of the title compound was 80% (106 g, >99% ee). MS (ESI): mass calcd. for C19H15ClF3N3O, 393.1; m/z found, 394.1 [M+H]+. 1H NMR (CDCl3, 500 MHz): 8.69 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.52-7.28 (m, 5H), 6.74 (s, 1H), 5.42 (brs, 1H), 5.10-4.98 (m, 1H), 3.92 (brs, 1H), 3.70-3.58 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[N:12]=[C:13]=[S:14])[CH3:2].Cl.C([O:18][C:19](=O)[CH2:20][NH:21][CH3:22])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[N:12]1[C:19](=[O:18])[CH2:20][N:21]([CH3:22])[C:13]1=[S:14])[CH3:2]
Reactant: CCOC(=O)CNC
Reactant: CCc1cccc(C(C)C)c1N=C=S
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1cccc(C(C)C)c1N1C(=O)CN(C)C1=S
Yield: 64.9 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 10.25 g of 2-ethyl-6-isopropylphenyl-isothiocyanate, 7.68 g of sarcosine ethyl ester hydrochloride, 14.8 g of triethyl amine, and 200 mL of chloroform. Crystallization from diethyl ether/hexane mixture afforded the title compound (8.95 g) as a tan solid, m.p. 132°-134° C. Anal. Calcd. for C15H20N2O S: C, 65.18; H, 7.29; N, 10.13. Found: C, 65.11; H, 7.31; N, 10.05. Mass spectrum (PBEI, M.+) m/z 276.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:10]1[C:18]([NH2:19])=[C:17]2[C:13]([N:14]=[CH:15][NH:16]2)=[N:12][CH:11]=1>N1C=CC=CC=1>[C:1]([NH:19][C:18]1[N:10]=[CH:11][N:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[N:14]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ncnc2nc[nH]c12)c1ccccc1
Reaction time: 3 h

Procedure:
Benzoyl chloride (1.3 mL, 11 mmol) was added dropwise over 30 min to a stirred suspension of adenine (1.35 g, 10 mmol) in dry pyridine, and stirring was continued at 100° C. for a further 3 h, and the reaction mixture was allowed to stand overnight at room temperature. The reaction was quenched with methanol and the solvents were removed under reduced pressure. The residue was triturated in hot isopropanol and dried in vacuo to give 8 as a white solid: yield 2.15 g (90%); MS (+ESI): m/z 240 [M+H]+; 1H NMR (400 MHz, d-DMSO): δ11.50 (s, 1H), 8.74 (s, 1H), 8.52 (s, 1H), 8.11 (d, 2H, J=7.2 Hz), 7.66 (t, 1H, J=7.2 Hz), 7.58 (t, 2H, J=7.2 Hz).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:26]1[CH2:29][CH:28]([CH2:30][C:31]([OH:33])=[O:32])[CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]3[CH2:29][CH:28]([CH2:30][C:31]([OH:33])=[O:32])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(O)CC1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(CC(=O)O)C3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (700 mg, 1.9 mmol), azetidin-3-ylacetic acid hydrochloride (495 mg, 3.3 mmol) and DIPEA (4 mL) in DMF (20 mL), provided the title compound as a crude product (600 mg, 70%), which was used directly in Step A.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[O:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][C:26](O)=[O:27]>>[Cl:18][C:14]1[CH:13]=[C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:26](=[O:27])[CH2:25][CH:21]3[CH2:22][CH2:23][CH2:24][O:20]3)[N:11]=2)[CH:17]=[CH:16][N:15]=1
Reactant: O=C(O)CC1CCCO1
Reactant: Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O
Product: O=C(CC1CCCO1)Nn1nc(-c2ccnc(Cl)c2)c2ccccc2c1=O

Procedure:
The product from Example 29B and 2-(tetrahydrofuran-2-yl)acetic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.46-11.62 (m, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.40-8.43 (m, 1H), 7.93-8.06 (m, 2H), 7.75-7.79 (m, 2H), 7.69 (dd, J=5.0, 1.5 Hz, 1H), 4.16 (p, J=6.7 Hz, 1H), 3.79 (td, J=7.7, 6.1 Hz, 1H), 3.63 (td, J=7.8, 6.4 Hz, 1H), 2.57 (dd, J=14.2, 6.9 Hz, 1H), 2.44-2.52 (m, 1H), 1.99-2.07 (m, 1H), 1.78-1.95 (m, 2H), 1.57-1.66 (m, 1H); MS (APCI+) M/Z 385 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn].[CH2:23]([C:30]1[O:31][C:32]([CH3:36])=[C:33]([CH3:35])[CH:34]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C:30]1[O:31][C:32]([CH3:36])=[C:33]([CH3:35])[C:34]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Reactant: Cc1cc(Cc2ccccc2)oc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Sn]
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin IV chloride (6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol) to give 22.0 g, of the title compound. 1H NMR δ 1.13 (t, 6 H), 1.83 (s, 3 H), 2.19 (s, 3 H), 2.61 (q, 4 H), 3.74 (s, 3 H), 3.82 (s, 2 H), 7.05 (d, 2 H), 7.23-7.27 (m, 3 H), 7.42 (s, 2 H). mass spectrum (EI), m/z 376 (M+).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 45.3 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 50 mg, 0.12 mmol) in acetonitrile (1.2 mL, 0.12 mmol) was added K2CO3 (48 mg, 0.35 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (30 mg, 0.13 mmol). The reaction mixture was heated to 45° C. for 15 hours, then cooled. After diluting in water, the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (24 mg, 48.0% yield). MS (apci) m/z=442.2 (M+H).
Reaction SMILES: Cl[CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[F:24][C:10]([F:9])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][N:20]([CH2:2][CH:3]3[O:7][C:6](=[O:8])[NH:5][CH2:4]3)[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1NCC(CCl)O1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: O=C1NCC(CN2CCN(c3cccc(C(F)(F)F)c3)CC2)O1

Procedure:
Following the procedure of Example 35, the title compound was prepared from 5-chloromethyl-2-oxazolidinone and 1-(3-trifluoromethylphenyl)piperazine, mp 122°-124° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[C:12]1([NH:18][C:19](=O)[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:8][C:7]1[C:2]2[N:18]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:19]([CH3:20])=[N:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Product: Cc1nc2cccc(Cl)c2n1-c1ccccc1
Yield: 66.7 %

Procedure:
Method A applied to 2,3-dichloronitrobenzene (96 mg, 0.5 mmol) and N-phenylacetamide (81 mg, 0.6 mmol) yielded the title compound as a brown solid (81 mg, 67%). mp 103-105° C. 1H NMR (DMSO) δ 2.38 (s, 3H), 7.30-7-33 (m, 2H), 7.56-7.62 (m, 5H), 7.70 (dd, J=5.4, 3.7Hz, 1H); 13C NMR δ 13.2, 115.9, 116.0, 124.5, 125.0, 128.7, 129.3, 130.2, 134.6, 138.9, 153.7, 158.5. HRMS (FAB): cal. for C14H12N2Cl [M+H+]: 243.0689; found: 243.0683.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[C:21]([O:25][C:26]([NH:28][CH:29]1[C:33]2([CH2:35][CH2:34]2)[CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[C:21]([O:25][C:26]([NH:28][CH:29]1[C:33]2([CH2:34][CH2:35]2)[CH2:32][N:31]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:18])[C:8]([C:15]([OH:17])=[O:16])=[CH:9][N:10]3[CH:12]3[CH2:14][CH2:13]3)=[CH:5][C:4]=2[F:19])[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)NC1CNCC12CC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC12CC2
Yield: 74.6 %

Procedure:
200 mg of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 150 mg of compound 11 and 70 mg of triethylamine were added to 5 ml of acetonitrile and the mixture was refluxed for 24 hours. After cooling, the solvent was removed under reduced pressure and to the residue was added water. The precipitate was collected by filtration and washed successively with water, acetonitrile, ethanol and ether and dried. The procedure gave 245 mg of 7-(7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptan-5-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid melting at 205°-207° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:12])=[N:8][C:9]=2Cl)[N:4]=[CH:3]1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[Cl:12][C:7]1[N:6]=[C:5]2[C:10]([N:2]([CH3:1])[CH:3]=[N:4]2)=[C:9]([NH:19][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[N:8]=1
Reactant: NC1CCCCC1
Reactant: Cn1cnc2nc(Cl)nc(Cl)c21
Product: Cn1cnc2nc(Cl)nc(NC3CCCCC3)c21

Procedure:
Was prepared according to Example 4 from 7-methyl-2,6-dichloro-7H-purine and cyclohexylamine.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[CH:12][N:13]=2)[CH:10]=1)[NH2:4].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=O)=[CH:17][N:16]=1.N>>[Cl:14][C:15]1[N:16]=[CH:17][C:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[N:9]([CH:11]=[CH:12][N:13]=4)[CH:10]=3)[N:4]=2)=[CH:22][CH:23]=1
Reactant: NC(=NO)c1ccc2nccn2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: N
Product: Clc1ccc(-c2nc(-c3ccc4nccn4c3)no2)cn1

Procedure:
The title compound was prepared according to Method D using N′-hydroxyimidazo[1,2-a]pyridine-6-carboximidamide (Bionet) and 6-chloronicotinoyl chloride (Aldrich). 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=1.2 Hz, 1 H), 7.74-7.84 (m, 2 H), 7.87 (d, J=8.3 Hz, 1 H), 8.20 (s, 1 H), 8.59 (dd, J=8.5, 2.6 Hz, 1 H), 9.20 (dd, J=2.4, 0.8 Hz, 1 H), 9.47 (t, J=1.4 Hz, 1 H) ppm; MS (DCI/NH3) m/z 298 (M+H)+, 300 (M+H)+.