Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[C:10]([C:27]2[N:31](C(OC(C)(C)C)=O)[C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]=3[N:28]=2)=[N:11][C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH:20]=2)=[CH:13][N:14]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[C:29]2[CH:42]=[CH:41][CH:40]=[CH:39][C:30]=2[N:31]=[C:27]1[C:10]1[C:9]([NH2:8])=[N:14][CH:13]=[C:12]([C:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:19][CH:20]=2)[N:11]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C2=CCN(c3ccccc3)CC2)nc1-c1nc2ccccc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2=CCN(c3ccccc3)CC2)nc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 14.5 %

Procedure:
A solution of tert-butyl 2-(3-(bis(tert-butoxycarbonyl)amino)-6-(1-phenyl-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-1H-benzo[d]imidazole-1-carboxylate (100 mg, 0.1495 mmol) in DCM (1 mL) was treated with TFA (1 mL, 12.98 mmol) and allowed to stir at ambient temperature for 40 minutes. The reaction was concentrated in vacuo and the resultant residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a pale brown solid (8.0 mg, 14% Yield). 1H NMR (400.0 MHz, DMSO) d 2.84 (2H, m), 3.53 (2H, m), 3.94 (2H, m), 6.76-6.90 (3H, m), 7.20-7.69 (6H, m), 7.70-9.39 (4H, m), 12.88 (1H, m) ppm; MS (ES+) 369.02
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[C:10]([OH:16])[CH:9]=1)[CH2:6][CH3:7])[CH3:4].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O1CCCC1>[CH2:3]([N:5]([C:8]1[CH:15]=[CH:14][C:11]2[CH:12]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[O:16][C:10]=2[CH:9]=1)[CH2:6][CH3:7])[CH3:4]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(CC)c1ccc2cc(C(=O)OC)oc2c1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
To a 250 mL three necked, round bottom flask equipped with a mechanical stirrer, reflux condenser, and Y-tube with a rubber septum and nitrogen inlet was added 1.8 gm (45 mmol) of 60% sodium hydride in mineral oil. After washing twice with 20 mL of hexanes, 150 mL of THF was added, followed by the rapid dropwise addition via transfer syringe of 3.86 gm (20 mmol) of 4-(N,N diethylamino)-2-hydroxybenzaldehyde, dissolved in 50 mL of tetrahydrofuran (THF). The flask was placed in an 80° C. oil bath and stirred vigorously for 5 minutes, at which time 2.08 mL (20 mmol) of methyl bromoacetate was added in one portion. Sodium bromide precipitated from solution and vigorous stirring had to be maintained throughout. The suspension was refluxed for 80 minutes, allowed to cool to room temperature, and diluted with 75 mL of diethyl ether. The reaction was quenched by the slow dropwise addition of 50 mL of dilute aqueous ammonium chloride. The phases were separated and the aqueous phase extracted with 100 mL of diethyl ether (Et2O). The combined organic phases were washed with 20 mL 1N NaOH and 20 mL water. After drying (MgSO4), the solvent was removed by rotary evaporation and the residual oil purified by flash chromatography (CH2Cl2 ; SiO2, 11/2×15") to yield 2.23 gm (45.3%) of the product as a colorless oil. Field desorption mass spectrum: m/e 247 (M+). Anal. calcd. for C14H17NO3 : C, 68.0., H, 6.9; N, 5.7. Found: C, 67.9; H, 6.8; N, 5.8. 1H 270 NMR (CDCl3): δ 6.7 (m, 2H, ArHa,b), 7.4 (m, 2H, ArHc,d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[CH3:14][N:15]1[CH2:21][C:19](=[O:20])[NH:18][C:16]1=[O:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:21]2[N:15]([CH3:14])[C:16](=[O:17])[NH:18][C:19]2=[O:20])[CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: CN1CC(=O)NC1=O
Product: COc1cc(C=C2C(=O)NC(=O)N2C)cc(OC)c1O
Yield: 33.5 %

Procedure:
Prepared according to the procedure described in Example 99 using 3,5-dimethoxy-4-hydroxybenzaldehyde (5.8 g, 31 mmoles) and 1-methyl hydantoin (3.5 g, 30 mmoles). Recrystallization from ethanol gave the pure product (2.8 g),mp 194°-196° C.
Reaction SMILES: [F:1][CH:2]([F:42])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:11]3[N:16]=[N:15][N:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[C:12]=3[N:13]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:42][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:11]3[N:16]=[N:15][N:14]([CH:17]4[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]4)[C:12]=3[N:13]=2)[C:6]2[CH:36]=[CH:37][CH:38]=[C:39]([O:40][CH3:41])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)c2nnn(C3CCNCC3)c2n1
Yield: 85.4 %

Procedure:
Reaction of the above carbamate (158 mg, 0.270 mmol) with an excess of TFA (2 mL) in CH2Cl2 (10 mL) at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3-(4-piperidinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (112 mg, 85%), which was used in the next step without further purification: 1H NMR (CDCl3) δ 7.83 (dd, J=8.4, 0.4 Hz, 1H), 7.46 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 4.87 (tt, J=11.7, 4.2 Hz, 1H), 4.80 (br s, 2H), 4.15 (br s, 2H), 4.07 (s, 3H), 3.92 (d, J=15.0 Hz, 4H), 3.34 (m, 2H), 2.88 (dt, J=12.7, 2.5 Hz, 2H), 2.38 (dq, J=12.0, 4.2 Hz, 2H), 2.18 (m, 2H).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C@@H:8]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:21])([CH3:20])[C@H:9]1[OH:22])[CH2:5][CH3:6])#[N:2].[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>N1C=CC=CC=1>[C:1]([N:3]=[C:4]([NH:7][C@@H:8]1[C:13]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:12]=2[O:11][C:10]([CH3:21])([CH3:20])[C@H:9]1[O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:5][CH3:6])#[N:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Solvent: c1ccncc1
Product: CCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of trans-4-[N-[1-(cyanoimino)propyl]amino]-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (1.49 g) in dry pyridine (7.5 ml) was added dropwise mesyl chloride (0.77 g) under ice-water cooling. The resulting mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and washed with 5% hydrochloric acid (twice), aqueous sodium bicarbonate and brine, successively. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethanol to give trans-4-[N-[1-(cyanoimino)propyl]amino]-3,4-dihydro-2,2-dimethyl-3-mesyloxy-2H-1-benzopyran-6-carbonitrile (1.50 g).
Reaction SMILES: [OH:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[O:23]C>Br>[OH:23][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:2]=1[OH:1])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1)=[O:7]
Reactant: COc1cc(C(=O)c2ccc(C(F)(F)F)cc2)cc([N+](=O)[O-])c1O
Agent: Br
Product: O=C(c1ccc(C(F)(F)F)cc1)c1cc(O)c(O)c([N+](=O)[O-])c1
Reaction time: 18 h

Procedure:
2.0 g of 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolved in 20 ml of 33 percent hydrobromic acid in glacial acetic acid) are stirred at 90° for 18 hours. Thereupon. 20 ml of 48 percent aqueous hydrobromic acid are added thereto, whereupon the mixture is stirred at 110° for an additional 18 hours. The reaction mixture is subsequently evaporated under reduced pressure and the residue is recrystallized from water. There is obtained 3,4-dihydroxy-5-nitro-4'-(trifluoromethyl)benzophenone of melting point 116°-118°.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:35])[C@H:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21](C(OC(C)(C)C)=O)[CH:22]=[C:23]([C:24]([O:26]C)=[O:25])[C:16]=23)[C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:6][C:7](=[O:35])[C@H:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[C:23]([C:24]([OH:26])=[O:25])[C:16]=23)[C@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H](C)[C@@H](NCc1ccnc2c1c(C(=O)OC)cn2C(=O)OC(C)(C)C)C(=O)NC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@@H](C)[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)NC1CCCC1
Temperature: 53 °C
Reaction time: 16 h

Procedure:
To crude 1-tert-butyl 3-methyl 4-(((2R,3R)-1-(cyclopentylamino)-3-methyl-1-oxopentan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate was added MeOH (1 mL) and aqueous NaOH (12N, 2mL). The reaction mixture was stirred at 53° C. for 16 h and then purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound. [M+H] calc'd for C20H28N4O3, 373; found, 373.7.
Reaction SMILES: [NH2:1][C:2](=[O:20])[C@@H:3]([NH:12]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C@@H:3]([CH2:4][C:5]1[CH:6]=[N:7][C:8]([Br:11])=[CH:9][CH:10]=1)[C:2]([NH2:1])=[O:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)nc1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1ccc(Br)nc1
Reaction time: 0.5 h
Yield: 94 %

Procedure:
(S)-tert-Butyl 1-amino-3-(6-bromopyridin-3-yl)-1-oxopropan-2-ylcarbamate (1.5 g) was dissolved in DCM (20 mL) and to the solution was added TFA (10 mL). The reaction mixture was stirred for 0.5 h then concentrated in vacuo. Crude material was dissolved in methanol and loaded onto an SCX cartridge. Non-basic impurities were washed off with methanol, then product was eluted with 10% ammonia in methanol to give the sub-title compound (1.0 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Cl:22]N1C(=O)CCC1=O>O1CCOCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[C:14]([NH:16][C:17]2[S:18][C:19]([Cl:22])=[CH:20][N:21]=2)[CH:13]=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2nccs2)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Nc2ncc(Cl)s2)n1
Temperature: 25 °C

Procedure:
2 g of 6-(((tert-butyl(dimethyl)silyl)oxy)methyl)-N-thiazol-2-ylpyridin-2-amine obtained in Example 5-(2) was dissolved in 20 ml of 1,4-dioxane, and then 832 mg of N-chlorosuccinimide was added thereto at room temperature. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, diluted with ethyl acetate, and then washed with water and brine. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([S:10]([CH2:13][S:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])(=[O:12])=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C1(C)C=CC(S([N:35]=[N+:36]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([S:10]([C:13]([S:14]([CH:17]2[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][CH2:22]2)(=[O:16])=[O:15])=[N+:35]=[N-:36])(=[O:12])=[O:11])[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCC)CC2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCC)CC2)CC1
Yield: 49 %

Procedure:
Synthesis was conducted as in Synthesis Example 8 using 8.0 g (0.020 mol) of the bis(4-n-propylcyclohexyl-sulfonyl)methane prepared above, 6.1 g (0.030 mol) of p-toluenesulfonylazide, 73 g of dichloromethane and 3.1 ml (0.020 mol) of DBU. There was obtained 4.1 g of the desired bis(4-n-propylcyclohexylsulfonyl)diazomethane. The yield was 48%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:11].[CH2:12]1CCN2C(=NCCC2)CC1.IC>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:12])=[O:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:11]
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C(O)c1cncc(F)c1Cl
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cncc(F)c1Cl
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
To a solution of 4-chloro-5-fluoronicotinic acid (1.7 g, 9.68 mmol) in acetonitrile (18 mL) cooled to 0° C. was added DBU (3.65 mL, 24.21 mmol) dropwise. The reaction mixture was stirred for 30 min. To this mixture iodomethane (3.03 mL, 48.4 mmol) was added dropwise and stirred at rt for 12 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel column chromatography (hexane and ethyl acetate) to afford methyl 4-chloro-5-fluoronicotinate (1.2 g, 6.33 mmol, 65% yield) as a yellow solid. LC/MS (ESI) m/e 190.0 [(M+H)+, calcd for C7H6ClFNO2 189.9]; LC/MS retention time (method D): tR=0.77 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:27][C@@H:26]([CH2:28][OH:29])[N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:17]5[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:30])[CH2:3][CH2:2]1.[CH3:31]I.[H-].[Na+]>>[CH:1]1([CH2:4][N:5]2[CH2:27][C@@H:26]([CH2:28][O:29][CH3:31])[N:8]3[C:9]4[CH:10]=[CH:11][C:12]([O:16][CH:17]5[CH2:18][CH2:19][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:22]5)=[CH:13][C:14]=4[CH:15]=[C:7]3[C:6]2=[O:30])[CH2:3][CH2:2]1
Reactant: CI
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](CO)CN(CC3CC3)C2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: COC[C@@H]1CN(CC2CC2)C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n21
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 17, from (S)-2-cyclopropylmethyl-4-hydroxymethyl-8-(1-isopropyl-piperidin-4-yloxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 75), methyl iodide and sodium hydride, to give the desired product as a colorless oil (67%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].O.[CH2:5]([O:7][C:8](=[O:19])/[C:9](=[CH:15]\OCC)/[C:10](=O)[CH:11]([F:13])[F:12])[CH3:6]>C1(C)C(C)=CC=CC=1>[F:12][CH:11]([F:13])[C:10]1[C:9]([C:8]([O:7][CH2:5][CH3:6])=[O:19])=[CH:15][N:2]([CH3:1])[N:3]=1
Reactant: CNN
Reactant: CCO/C=C(\C(=O)OCC)C(=O)C(F)F
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)c1cn(C)nc1C(F)F
Reaction time: 0.25 h

Procedure:
A 0.25 mol solution of methylhydrazine 40% diluted in 50.0 g xylene and 4.7 g water was prepared. A solution of 0.25 mol of 2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethyl ester in 100.0 g xylene was added to the methylhydrazine over 30-60 minutes at a temperature of 20-25° C. The reaction mixture was stirred for 15 min. The phases of the reaction mass were separated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][CH2:17][CH2:18]O)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(Cl)([Cl:22])=O>>[Cl:22][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCl
Yield: 99.6 %

Procedure:
Using the general method of Example 19 Part A, 4-[(3-nitroquinolin-4-yl)amino]butan-1-ol (120 g, 0.459 mol) was chlorinated with thionyl chloride (109 g, 0.919 mol) to provide 127.9 g of N-(4-chlorobutyl)-3-nitroquinolin-4-amine as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]4[O:21][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[N:19][N:18]=4)[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)[N:3]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43].CCN(CC)CC.[OH-].[Na+]>CN1C(=O)CCC1>[CH:23]([NH:22][C:20]1[O:21][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[C:8]3[C:4]2[N:3]=[C:2]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[C:38](=[O:43])[CH2:39]3)[CH:7]=[CH:6][N:5]=2)=[N:18][N:19]=1)([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nccc(Cl)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: CN1CCNCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CC(C)Nc1nnc(-c2ccc3[nH]cc(-c4nccc(N5CCN(C)C(=O)C5)n4)c3c2)o1
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-(4-chloropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-N-isopropyl-1,3,4-oxadiazol-2-amine (80 mg, 0.157 mmol) and 1-methylpiperazin-2-one (17.94 mg, 0.157 mmol) in NMP (1.0 mL), followed by Et3N (65.6 μL, 0.472 mmol, Aldrich). The reaction was stirred and heated in a Initiator microwave reactor at 100° C. for 30 min. Then aq. NaOH (5 M, 0.3 mL) was added and the reaction was heated in microwave at 100° C. for 20 min. The mixture was purified with RP-HPLC (eluent: 10-60% MeCN in water with 0.1% TFA) and the fractions containing the product were combined and concentrated to remove AcCN. The remaining mixture was neutralized with sat. NaHCO3 and extracted with CHCl3/iPrOH (4:1). The combined organic layers were dried, filtered and concentrated to give 4-(2-(5-(5-(isopropylamino)-1,3,4-oxadiazol-2-yl)-1H-indol-3-yl)pyrimidin-4-yl)-1-methylpiperazin-2-one (30.0 mg, 0.069 mmol, 44.1%) as a light yellow solid. MS (ESI, pos. ion) m/z: 433.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (1H, br. s.), 9.10 (1H, s), 8.30 (1H, d, J=6.1 Hz), 8.23 (1H, d, J=2.7 Hz), 7.60-7.73 (2H, m), 7.56 (1H, d, J=8.4 Hz), 6.69 (1H, d, J=6.1 Hz), 4.40 (2H, br. s.), 3.93 (2H, br. s.), 3.75 (1H, dq, J=13.3, 6.5 Hz), 3.51 (2H, t, J=5.2 Hz), 2.97 (3H, s), 1.25 (6H, d, J=6.8 Hz), 1.24 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: CO
Reactant: O=C(O)Cc1cc(O)ccc1Br
Agent: Cl
Product: COC(=O)Cc1cc(O)ccc1Br
Temperature: 70 °C

Procedure:
To (2-bromo-5-hydroxy-phenyl)-acetic acid (1.5 g, 6.5 mmol) in MeOH (15 mL) was added HCl (4N in 1,4-dioxane; 3 mL), and the solution was heated to 70° C. for 8 hours. The mixture was concentrated to give the desired product as a white solid (1.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[N:24]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:30]3[CH:29]=[C:28]4[C:33](=[CH:32][CH:31]=3)[N:24]=[CH:25][CH:26]=[CH:27]4)=[CH:16][C:15]=2[CH:21]=[O:22])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(Br)cc2C=O)c1
Reactant: CC1(C)OB(c2ccc3ncccc3c2)OC1(C)C
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3ccc4ncccc4c3)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: (4′-bromo-2′-formyl-6-methoxy-biphenyl-3-yl)-acetic acid ethyl ester and 6-quinolineboronic acid pinacol ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5]Br.[Br:10][C:11]1[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][N:14]1[CH:15]=[CH:16][C:11]([Br:10])=[CH:12][C:13]1=[O:17]
Reactant: COC(=O)C(C)(C)CBr
Reactant: O=c1cc(Br)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)Cn1ccc(Br)cc1=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added to a mixture of 4-bromo-1H-pyridin-2-one (0.55 g) and potassium carbonate (0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The mixture was heated to 60° C. and stirred at this temperature overnight. After stirring at 80° C. for another 8 h, the mixture was cooled to room temperature and water was added. The resultant mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried (MgSO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g (32% of theory); Mass spectrum (ESI+): m/z=288/300 (Br) [M+H]+.
Reaction SMILES: [OH-].[Na+].Cl.Cl.[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH2:15][S:16][C:17](=N)N)[CH:6]=1.BrC[CH2:22][CH2:23][Cl:24]>O>[Cl:24][CH2:23][CH2:22][CH2:17][S:16][CH2:15][C:7]1[CH:6]=[N:5][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: N=C(N)SCc1cnc2ccccc2c1
Reactant: ClCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cnc2ccccc2c1
Temperature: 70 °C
Reaction time: 20 h
Yield: 17.9 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (40.8 cc) is added in the course of 9 minutes, and whilst allowing the temperature to rise to 10° C., to a solution, cooled to 1° C., of 2-(quinol-3-ylmethyl)-isothiourea dihydrochloride (59.2 g) in distilled water (100 cc). After heating for 20 minutes at a temperature of about 70° C. and then cooling to 12° C., a 10 N aqueous solution of sodium hydroxide (25 cc) is added dropwise in the course of 5 minutes. 1-Bromo-3-chloropropane (33.6 g) is then added and stirring is continued for 20 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (400 cc in total). The organic extracts are combined, washed with distilled water (100 cc), dried over anhydrous sodium sulphate and concentrated under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. so as to bring the volume to about 100 cc. The solution thus obtained is chromatographed on neutral silica gel (250 g) contained in a column of diameter 3.8 cm. Elution is carried out with methylene chloride (1500 cc), one 600 cc fraction and one 900 cc fraction being collected. The latter fraction is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Quinol-3-ylmethyl 3-chloropropyl sulphide (9.2 g) is thus obtained in the form of a yellow oil.
Reaction SMILES: [Na].[C:2]([C:4]1[C:5](=[O:22])[NH:6][N:7]=[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:3].[CH3:23][N:24]([CH3:28])[C:25](Cl)=[O:26].O>CN(C)C=O>[CH3:23][N:24]([CH3:28])[C:25]([N:6]1[C:5](=[O:22])[C:4]([C:2]#[N:3])=[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:7]1)=[O:26]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: CN(C)C(=O)Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)n1nc(-c2ccccc2)c(-c2ccccc2)c(C#N)c1=O
Temperature: 110 °C

Procedure:
5.0 grams (0.016 mole) of the sodium salt of 4-cyano-5,6-diphenyl-3-(2H)-pyridazinone was reacted with 1.83 grams (0.017 mole) of dimethylcarbamyl chloride in 50 mls of dimethylformamide. This solution was heated 110° C. for 3 hours, cooled, and poured into excess water. The precipitant solid was filtered, washed with water and air dried. This solid was taken up in chloroform, dried over sodium sulfate and the solvent distilled at reduced pressure. The residual solid was recrystallized from ethyl alcohol to give 3.0 grams of a solid which melted at 231° C. The infrared spectrum showed the methyl group at 3.5μ, the nitrile band at 4.5μ, and two carbonyl bands at 5.8 and 6.0μ.