Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([C:8](=[N:20]O)[C:9](=O)[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[CH3:23][NH:24][NH2:25]>CO>[NH2:20][C:8]1[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:25][N:24]([CH3:23])[C:9]=1[C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18]
Reactant: CCOC(=O)C(=O)C(=NO)C(=O)c1c(C)cc(C)cc1C
Reactant: CNN
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1nn(C)c(-c2c(C)cc(C)cc2C)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
To a solution of the product of step B (4.0 g, 13.8 mmol) and 1.6 mL of 12N hydrochloric acid in 100 mL of methanol was added dropwise 0.63 g of methyl hydrazine at 0° C. The reaction mixture was stirred at room temperature 4 hours, and then concentrated. The resulting residue was partitioned between water and ethyl acetate. The organic phase was separated and washed once with brine. The ethyl acetate solution was then mixed with 100 mL of water. Solid Na2S2O4 in excess was added in small portion until TLC showed completion of the reduction. The organic phase was separated, washed with water and brine, and dried over Na2SO4. Evaporation gave 3.1 g of the title compound as a foam.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.O>O1CCCC1>[F:14][C:15]([F:24])([F:25])[C:16]1[CH:17]=[C:18]([CH2:19][CH2:5][CH2:3][NH2:4])[CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NCCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.6 %

Procedure:
To an ice-bath cooled suspension of sodium hydride (1.32 g of a 60% dispersion in oil, 33 mmol) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere was added dropwise a solution of diethyl cyanomethylphosphonate (5.34 ml, 33 mmol) in tetrahydrofuran (40 ml) and the resulting mixture stirred at 0° C. for 15 minutes. To this mixture was added a solution of 3-trifluoromethylbenzaldehyde (5.22 g, 30 mmol) in anhydrous tetrahydrofuran (40 ml) and the resulting mixture stirred at room temperature for 1.5 hours. Water (300 ml) was added and the mixture extracted with ethyl acetate (3×150 ml). The combined organic layers were washed with water (2×200 ml), brine (150 ml) then dried (Na2SO4) and evaporated. The residue was taken up in a mixture of ethanol (100 ml) and ammonium hydroxide (25 ml) and hydrogenated according to the method of Description 2. Purification by column chromatography on silica eluting with 5% MeOH in dichloromethane+0.5% NH4OH gave the title compound (1.5 g, 25%) as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([C:12]([O:14]CC)=[O:13])[NH:5][N:4]=1.[C:19](=O)([O-])[O-].[K+].[K+].IC.[OH-].[Na+]>CC(C)=O.O>[CH3:19][N:5]1[C:6]([C:12]([OH:14])=[O:13])=[C:7]([C:8]([F:11])([F:10])[F:9])[C:3]([C:2]([F:18])([F:17])[F:1])=[N:4]1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CI
Product: Cn1nc(C(F)(F)F)c(C(F)(F)F)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.0 g (10.9 mmol) of ethyl 3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylate and 4.5 g (32.6 mmol) of potassium carbonate are suspended in 70 ml of acetone, and 1.35 ml of iodomethane (21.7 mmol) are added. The reaction mixture is stirred at room temperature overnight. 54 ml (108 mmol) of 2 N aqueous sodium hydroxide solution are added to the suspension. The solution is then stirred at room temperature overnight. The reaction mixture is diluted with water, and most of the acetone is removed on a rotary evaporator under reduced pressure. The residue is adjusted to pH 2-3 using 1 M hydrochloric acid. The aqueous reaction solution is extracted twice with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure on a rotary evaporator. This gives 2.7 g of 1-methyl-3,4-bis(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (84%; purity 88%) as a brown solid.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C1C(=O)N([I:23])C(=O)C1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[C:27]([O:34][CH3:35])[CH:26]=1>OS(O)(=O)=O>[Cl:24][C:25]1[CH:26]=[C:27]([O:34][CH3:35])[C:28]([N+:31]([O-:33])=[O:32])=[CH:29][C:30]=1[I:23]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 163.9 %

Procedure:
To a solution of H2SO4 (600 mL, 90%), trifluoromethanesulfonic anhydride (11.3 g, 0.04 mol) and NIS (49.68 g, 0.22 mol) were added and resulting mixture was stirred at room temperature for 1 h. To this mixture, 4-chloro-2-methoxy-1-nitrobenzene (69 g, 0.368 mol) was added quickly. The mixture was stirred for 1 h, and then NIS (33.12 g, 0.148 mol) was slowly added to the mixture. The mixture was stirred at room temperature for 1 h and then was poured into ice-water. The precipitate collected by filtration, rinsed with water, aqueous NaSO3 and NaHCO3 solutions, and then dried in vacuo to afford the desired product (113 g, 98% yield).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C(Cl)Cl>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][CH:12]=[O:11])[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A solution of oxalyl chloride (1.23 mL, 14.1 mmol) in methylene chloride (50 mL) was cooled to −78° C. DMSO (2.0 mL, 28.3 mmol), was added slowly via syringe. After 10 min, 4-(2-hydroxyeth-1-yl)-1-t-butoxycarbonylpiperidine (2.7 g, 11.8 mmol) in methylene chloride (15 mL) was added. The cold mixture was stirred for an additional 20 min then TEA (8.2 mL, 59 mmol) was added. The mixture was warmed to rt and stirred for 1.5 h, then diluted with methylene chloride (300 mL). The organic phase was washed with 1M sodium hydroxide, dried over sodium sulfate and concentrated. FC (125 g silica, 2.5/1 hexanes/ethyl acetate) afforded the title compound (2.25 g).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([CH2:36][C:37](=[O:39])[CH3:38])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(=O)Cc1ccc(O)cc1
Product: CC(=O)Cc1ccc(OCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of 4-hydroxyphenylpropanone are treated as described in Example 76.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:12][C:13]([F:21])([F:20])[C:14]([F:19])([F:18])[CH2:15][CH2:16]I.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:16][CH2:15][C:14]([F:19])([F:18])[C:13]([F:21])([F:20])[F:12])[C:5]2=[N:6][CH:7]=1
Reactant: FC(F)(F)C(F)(F)CCI
Reactant: Fc1cnc2[nH]nc(I)c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: Fc1cnc2c(c1)c(I)nn2CCC(F)(F)C(F)(F)F
Temperature: 140 °C
Reaction time: 8 h

Procedure:
5.0 g (19.010 mmol) of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine were initially charged in DMF (100 ml), and then 20.83 g (76.042 mmol) of 1,1,1,2,2-pentafluoro-4-iodobutane, and also 14.86 g (45.65 mmol) of cesium carbonate and 0.63 g (3.802 mmol) of potassium iodide were added. The mixture was stirred at 140° C. overnight. The mixture was then cooled and combined with a prior experiment which proceeded analogously from 200 mg of 5-fluoro-3-iodo-1H-pyrazolo[3,4-b]pyridine. Solids were filtered off with suction and washed with DMF, and then the liquid was concentrated under high vacuum. The residue was purified by means of preparative HPLC (methanol:water gradient). This gave 4.34 g (52% of theory) of the title compound in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[C:35]([O:43][C:44]([F:47])([F:46])[F:45])[CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:39]([C:36]1[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][C:35]=1[O:43][C:44]([F:45])([F:46])[F:47])(=[O:41])=[O:40])[C:6](=[O:11])[C:5]2([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]1[C:26]([N:28]([CH3:29])[CH3:30])=[O:27])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N2CCCC[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3CCCC[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 40.4 %

Procedure:
With 500 mg of (2S)-1-[5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-N,N-dimethylpiperidine-2-carboxamide, which is the compound described in Preparation 3.49 (Isomer B) of Publication No. WO01/98295 and 374 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 322 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[N:17]1([CH2:23][CH2:24][CH2:25][Cl:26])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:26].[N:17]1([CH:23]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][NH:9]3)[CH2:24][CH3:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Product: CCC(c1cccc2[nH]nc(-c3ccccc3)c12)N1CCCCC1
Yield: 74.5 %

Procedure:
By the procedure similar to that described in Example 1, 3-phenylindazole (3.88 g) and piperidinopropyl chloride hydrochloride (5.94 g) were treated to obtain 5.3 g of 1-piperidinopropyl-3-phenylindazole hydrochloride (m.p. 201°-202° C).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(C)c1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1Br
Temperature: 5 °C
Yield: 58 %

Procedure:
2-Bromo-3-methylanisole (2.02 g, 1.00 mmol) and N-bromosuccinimide in carbon tetrachloride (25 ml) were heated to reflux over a 150 W light bulb for 2 h. The solution was cooled to 5° C., filtered and evaporated to drynes under reduced pressure. Purification by flash chromatography using hexane/dichloromethane (8:1) as eluent gave the title compound (162 g, 58%) as a white low melting point solid; δH (CDCl3) 3.90 (3H, s, OCH3), 4.64 (2H, s, CH2Br), 6.85 (1H, dd, J 8.2 and 1.3 Hz, 6-H), 7.08 (1H, dd, J 7.5 and 1.3 Hz, 4-H9, 7.23-7.30 (1H, m, 5-H): δC (CDCl3) 33.7 (CH2Br), 56.4 (OCH3), 111.8, 114.1 (C-2), 123.1, 128.3, 138.6 (C-1), 156.4 (C-3): m/z 282 (M+, 12%), 280 (M+, 13%). 199 (100%): (Found: M+, 277.8947. C8H8OBr2 requires M, 277.8942).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.[NH:12]([C:14](=[S:16])[NH2:15])[NH2:13].O=P(Cl)(Cl)Cl>C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]1[S:16][C:14]([NH2:15])=[N:12][N:13]=1
Reactant: O=C(O)c1ccc(I)cc1Cl
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc(I)cc2Cl)s1
Temperature: 78 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
A stirred mixture of 2-chloro-4-iodobenzoic acid (2 g, 7.08 mmol) and hydrazinecarbothioamide (0.968 g, 10.62 mmol) was cooled under nitrogen in an ice bath. POCl3 (1.98 mL, 21.24 mmol) was added drop-wise and the reaction mixture was heated at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath before quenching by addition of ice water (50 mL). The resulting solid/cake was sonicated for 1 hour to give a free stirring suspension. This material was left to slurry at room temperature for ˜18 hours then filtered under vacuum and rinsed with water to afford the crude product as a pale yellow/orange solid. The solid was re-suspended in saturated NaHCO3(aq) (50 mL), slurried at room temperature for 2 hours, then collected by vacuum filtration to afford the title compound as a pale yellow solid (2.05 g, 86% yield). LC-MS: Rt 1.20 min; MS m/z 337.8 [M]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (d, J=1.52 Hz, 1H), 7.76-7.82 (m, 2H), 7.50 (s, 2H).
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C1C(=O)N([Br:26])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+].O>CC(O)=O.C(Cl)(Cl)Cl>[Br:26][C:15]1[S:16][CH:17]=[CH:18][C:14]=1[C:2]1([OH:1])[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[CH2:3]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2)C1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccsc2Br)C1
Reaction time: 3 h
Yield: 83.4 %

Procedure:
To a solution of tert-butyl 3-hydroxy-3-(thiophen-3-yl)pyrrolidine-1-carboxylate (5 g, 18.6 mmol) in AcOH (10 mL) and CHCl3 (10 mL) at 0° C. was added NBS (5.0 g, 27.9 mmol) in portions. After stirring for 3 h, the reaction mixture was treated with Na2SO3 and water, followed by extraction with EtOAc. The combined organic layer was washed with brine, and dried over anhydrous Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the title compound (5.4 g, 84%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]1[O:27][CH:26]([CH3:28])[CH2:25][NH:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:24]3[CH2:23][CH:22]([CH3:21])[O:27][CH:26]([CH3:28])[CH2:25]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1CNCC(C)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)CC(C)O1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2,6-dimethylmorpholine (141-91-3) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.5 [MH+].
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.Cl[CH2:8][C:9]([O:11][CH3:12])=[O:10].[OH-].[K+]>CO>[CH3:12][O:11][C:9](=[O:10])[CH2:8][N:4]1[N:5]=[N:6][C:2]([NH2:1])=[N:3]1
Reactant: Nc1nnn[nH]1
Reactant: COC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Cn1nnc(N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
63.1 A solution of 8.5 g 5-amino-1H-tetrazole, 8.8 ml methyl chloroacetate and 5.8 g potassium hydroxide in 100 ml methanol was heated to reflux under an argon atmosphere and stirred for 18 h. A white solid slowly precipitated. The suspension was cooled to r.t. The white solid was filtered off and washed with methanol. The filtrate was concentrated. The residue was suspended in 100 ml EtOH and heated to reflux. After 1 h stirring at reflux, the mixture was filtered while hot. The filtrate was concentrated. The residue was recrystallized in 100 ml EtOH to give 1.8 g of (5-amino-tetrazol-2-yl)-acetic acid methyl ester as colorless crystalline solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](B(O)O)[CH:38]=2)[CH:33]=[CH:32]1>>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37]([C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]3)[NH:20][C:19]4=[O:29])[CH:38]=2)[CH:33]=[CH:32]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccc5cc[nH]c5c4)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and indole-6-boronic acid in step C. MS (ESI): mass calcd. for C20H13N5O3, 371.1; m/z found, 372.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 13.01 (s, 1H), 12.86 (s, 1H), 11.23 (s, 1H), 8.99 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.77 (s, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.43 (s, 2H), 6.48 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([CH2:27][CH2:28][CH2:29][NH:30][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH2:15])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCCCc1ccccc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: c1ccncc1
Product: Nc1nc2ccc(-c3ccnc(NCCCc4ccccc4)n3)cc2s1
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (54.1 mg, 178 μmol) and 3-phenylpropylamine (25.2 μl, 178 μmol) were suspended in pyridine (0.80 mL) and sealed in a microwave vial and heated in the CEM microwave (CEM Corporation, Matthews, N.C.) at 120° C. and 300 watts with a 5 minute ramp time and 20-minute run time. The reaction was cooled to RT, concentrated, and the resulting crude material was purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 30 minutes) to afford 6-(2-(3-phenylpropylamino) pyrimidin-4-yl)benzo[d]thiazol-2-amine. MS (ESI pos. ion) m/z: 362. Calculated exact mass for C20H19N5S: 361.
Reaction SMILES: [Br:1][C:2]1[C:11]([C@H:12]([OH:15])[CH2:13][OH:14])=[C:10]([CH3:16])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:17])=[N:7]2.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>ClCCl.N1C=CC=CC=1>[C:20]([O:14][CH2:13][C@H:12]([C:11]1[C:2]([Br:1])=[C:3]2[C:8](=[CH:9][C:10]=1[CH3:16])[N:7]=[C:6]([CH3:17])[CH:5]=[CH:4]2)[OH:15])(=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1ccc2c(Br)c([C@H](O)CO)c(C)cc2n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(Br)c([C@H](O)COC(=O)C(C)(C)C)c(C)cc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-1-(5-bromo-2,7-dimethylquinolin-6-yl)ethane-1,2-diol (290 mg, 0.98 mmol) in dichloromethane (12 mL) and pyridine (2 mL) was added trimethyl acetylchloride (0.24 mL, 1.97 mmol) at 0° C. The mixture was stirred at room temperature for 2 hours, and quenched with slow addition of NaHCO3 solution. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide (S)-2-(5-bromo-2,7-dimethylquinolin-6-yl)-2-hydroxyethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C18H23BrNO3: 380.1; Found: 380.2.
Reaction SMILES: CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[CH3:15][C@:16]12[CH2:32][CH2:31][C@H:30]3[C@@H:21]([CH2:22][CH2:23][CH:24]4[C@@H:29]3[CH2:28][CH2:27][C:26](=[O:33])[CH2:25]4)[C@@H:20]1[CH2:19][CH:18]=[CH:17]2.[OH-].[Na+].OO>C1COCC1.CCOCC.O>[CH3:15][C@:16]12[CH2:32][CH2:31][C@H:30]3[C@@H:21]([CH2:22][CH2:23][CH:24]4[C@@H:29]3[CH2:28][CH2:27][C@@H:26]([OH:33])[CH2:25]4)[C@@H:20]1[CH2:19][CH:18]=[CH:17]2
Reactant: C[C@@]12C=CC[C@H]1[C@@H]1CCC3CC(=O)CC[C@@H]3[C@H]1CC2
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: OO
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3C[C@H](O)CC[C@@H]3[C@H]1CC2
Reaction time: 1 h
Yield: 86.7 %

Procedure:
This synthesis is depicted in FIG. 11. L-Selectride (d, lithium tri(sec-butyl)hydridoborate, 4 ml of a 1 M solution in THF, 4 mmol) was added dropwise at 0° to a solution of ketone 10 (800 mg, 3.10 mmol) in dry ether (5 ml). After stirring for 1 h at 0°, water was added (10 ml). The boranes were oxidized by adding 10% aq. NaOH-solution (5 ml), followed by 30% aq. H2O2-solution (3 ml) and stirring for 3 h at RT. After workup (ether), the crude product (790 mg, Ca. 9:1 mixture of 11 and 12) was chromatographed on silica gel with CH2Cl2 to give 700 mg (87%) of pure alcohol 11. M.p. 119-120°→123-124° (from PE), [a]D +40.6° (C=1.0).—IR. (CHCl3): 3640m, 3500 br., 1585w.—1H-NMR. (90 MHz): 0.78 (s, 3 H); 4.09 (m, w½≈8, 1 H); 5.71 (m, 1 H), 5.87 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[CH:22]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].Cl[C:27](=[O:35])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[C:27](=[O:35])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4cc[nH]c34)no2)cc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred suspension of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D51) (0.5 g) and ZnCl2 (1.0 g) in DCM (50 mL) was added a solution of ethyl 4-chloro-4-oxobutanoate (2.3 g) in DCM (5 mL) dropwise. After stirring at room temperature overnight, the reaction mixture was washed with water and brine. The organic phase was separated and dried over anhydrous sodium sulphate. Filtration and concentration under vacuum afforded the crude product ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]-4-oxobutanoate (D52) as a brown solid (0.5 g). δH (CDCl3, 400 MHz): 1.27 (3H, t), 1.46 (6H, d), 2.68 (2H, t), 2.83 (2H, t), 3.29 (2H, q), 4.73 (1H, m), 7.07 (1H, d), 7.42 (1H, t), 8.06 (1H, s), 8.08 (1H, dd), 8.16 (1H, dd), 8.26 (1H, dd), 8.56 (1H, d), 10.27 (1H, s). MS (ES): C25H24ClN3O5 requires 481; found 482.2 (M+H+).
Reaction SMILES: [C:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][Cl:21])[CH:15]=2)=[O:13])=[N:8][C:7]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].C(OCC)(=O)C.Cl.[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][OH:40]>>[ClH:21].[C:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][O:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[CH:15]=2)=[O:13])=[N:8][C:7]=1[C:22]1[O:23][CH:24]=[CH:25][CH:26]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1sc(NC(=O)c2ccnc(CCl)c2)nc1-c1ccco1
Reactant: CN(C)CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCC(=O)c1sc(NC(=O)c2ccnc(COCCN(C)C)c2)nc1-c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
Compound 387 (247 mg, 0.635 mmol) was dissolved in 2-(dimethylamino)ethanol (3 mL), and 55% sodium hydride (55.0 mg, 1.27 mmol) was added thereto, followed by stirring at room temperature for 2 hours. The precipitated solid was collected by filtration to afford a free form of the entitled Compound. An ethyl acetate solution of 4 mol/L hydrogen chloride was added to the resulting free form, and the precipitated solid was collected by filtration to afford the entitled Compound 389 (248 mg, 82%).