Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H](C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12])=O)C(C)C.CN1C2C(=CC=CC=2)C(C)=C1C(O)=O.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[NH2:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cc1c(C(=O)O)n(C)c2ccccc12
Solvent: CN(C)C=O
Product: N[C@@H](CC(=O)O)C(=O)O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred turbid mixture of N-[valinyl]aspartic acid, α-methyl, β-tert-butyl diester 2.75 g, 9.11 mmol) and 1,3-dimethylindole-2-carboxylic acid (1.95 g, 10.3 mmol) in DMF (30 ml) was added 4-dimethylaminopyridine (DMAP) (1.26 g, 10.3 mmol) and EDAC (2.37 g, 12.4 mmol). The reaction mixture was stirred under a nitrogen atmosphere at 0° C. for 1 hour and at room temperature for 3 hours. The reaction mixture was then partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined extracts were washed with saturated NaHCO3 solution, water, and brine, dried over sodium sulfate, and concentrated to give a solid. The solid was triturated with ether to give N-[1,3-dimethyl-indole-2-cabonyl)valinyl]aspartic acid, α-methyl, β-tert-butyl diester as a white powder (2.87 g, 67%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][C:15]=2[CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[C:15]([CH3:39])[CH:16]=1)=[O:22]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.4 g) were added dichloromethane (63 ml) and trifluoroacetic acid (13 ml), stirred at room temperature for 2 hours, and then to the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling. The precipitated solid was washed with ethanol and water to give the titled compound (2.6 g) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]Br>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([OH:28])=[O:18])=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Reactant: COC(=O)c1ccccc1CBr
Product: O=C(O)c1ccccc1COc1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
2-(2′-Nitro-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4′-hydroxy-2-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 69 mg. Mass spectrum (ES) MH+=350.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17].O.[NH4+].[OH-]>C(O)C>[F:14][C:11]1[CH:12]=[C:13]2[C:5]([C:3]3[N:15]=[C:16]([NH2:18])[S:17][CH:2]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1c[nH]c2ncc(F)cc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1nc(-c2c[nH]c3ncc(F)cc23)cs1
Temperature: 70 °C
Yield: 82.3 %

Procedure:
Aluminum chloride (0.48 g, 3.6 mmol) was added slowly to a stirred solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.164 g, 1.2 mmol) in CH2Cl2 (5 mL)). Bromoacetyl bromide (0.1 mL, 1.5 mmol) was added and the resulting solution was heated at 50° C. for 1 h and cooled to room temperature. Water (25 mL) was added, the solution was basified with saturated NaHCO3 and the mixture was extracted with EtOAc (3×25 mL). The organic extracts were dried and concentrated under reduced pressure to give 2-bromo-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone as a pale brown solid. A mixture of 2-bromo-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone (0.28 g) and thiourea (0.13 g) in ethanol (10 mL) were heated at 70° C. for 1 h. Water (50 mL) was added and the solution was basified with concentrated NH4OH. The aqueous layer was extracted with EtOAc (3×25 mL). The organic extracts were dried and concentrated under reduced pressure to give 4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)thiazol-2-amine (0.21 g, 75%, 2 steps) as pale brown solid. Mass Spec.; MS 235 (M+1); 1H NMR(DMSO-d6, 500 MHz) δ 11.86(s, 1H), 8.27(d, 1H), 8.22(s,1H), 7.83(d,1H), 6.95(brs,2H), 6.81(s,1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[CH:17]=O)[CH:9]=2)[N:3]=1.[CH3:19][NH:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.CC(O)=O.N>C(O)C.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:13]=[N:12][CH:11]=[C:10]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[N:20]([CH3:19])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[N:27]=3)[CH:9]=2)[N:3]=1
Reactant: CNc1ccccc1N
Reactant: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3C=O)cnn2)n1
Agent: [Cu+2]
Agent: N
Agent: O=S(=O)([O-])[O-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nc(C)n(-c2cc([C@@H]3C[C@H]3c3nc4ccccc4n3C)cnn2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropanecarbaldehyde (23-6, 70 mg, 0.29 mmol, 1.0 eq.) and N1-methylbenzene-1,2-diamine (42 mg, 0.35 mmol, 1.2 eq.) in ethanol (1.5 mL) was added anhydrous CuSO4 (56 mg, 0.35 mmol, 1.2 eq.) and AcOH (21 mg, 0.35 mmol, 1.2 eq.). The mixture was stirred at room temperature for 4 hours then basified with 2 M NH3 in ethanol (1.0 mL). The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (70% acetone in hexanes) to afford trans-2-(2-(6-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)pyridazin-4-yl)cyclopropyl)-1-methyl-1H-benzo[d]imidazole (23-7) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 9.07 (d, 1H, J=2.1 Hz), 7.80 (d, 1H, J=2.1 Hz), 7.75-7.66 (m, 1H), 7.35-7.22 (m, 3H), 3.84 (s, 3H), 2.96 (s, 3H), 2.86 (m, 1H), 2.52 (m, 1H), 2.44 (s, 3H), 2.18 (m, 1H), 1.83 (m, 1H). LRMS m/z (M+H) 346.0 found, 346.4 required.
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[CH3:15])[CH2:3][CH2:2]1.[NH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:24][CH2:23]1)[C:18]([NH2:20])=[O:19]>>[C:18]([C@@H:17]([NH:16][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH3:15])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[CH2:21][CH:22]1[CH2:24][CH2:23]1)(=[O:19])[NH2:20]
Reactant: NC(=O)[C@@H](N)CC1CC1
Reactant: Cc1ccc(C(=O)O)nc1OCC1CC1
Product: Cc1ccc(C(=O)N[C@@H](CC2CC2)C(N)=O)nc1OCC1CC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-methyl-pyridine-2-carboxylic acid (Example 36 d) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=318.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[CH2:18]([OH:27])/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:27][CH2:18][CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OC/C=C/c1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCC=Cc2ccccc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, (E)-cinnamyl alcohol and DBU in DME. ES-MS m/e (%): 319 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[NH2:39][CH2:40][CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([NH:39][CH2:40][CH:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: NCC1CCOCC1
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(OS(=O)(=O)C(F)(F)F)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Solvent: CN(C)C=O
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(NCC4CCOCC4)n2)CN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
tert-Butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (250 mg, 0.45 mmol, example 69c) was dissolved in DMF (2 mL). 4-Aminomethyltetrahydropyran (51.9 mg, 0.45 mmol) was added and the reaction mixture was stirred at 85° C. overnight. The reaction was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was purified by flash column chromatography using dichloromethane and methanol as eluent yielding tert-butyl 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (62.0 mg, 26.5%). MS (ES+) m/z 520.4 (M+H)+
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4](I)[CH:3]=1.[CH3:18][C:19]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][N:26]=2)[CH2:21][CH2:20]1.CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:28]2[CH:27]=[N:26][C:25]([N:22]3[CH2:23][CH2:24][C:19]([CH3:18])([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:20][CH2:21]3)=[N:30][CH:29]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(Br)c2s1
Reactant: CCOC(=O)C1(C)CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Temperature: 80 °C
Yield: 41.2 %

Procedure:
To a solution of Intermediate 3 (22.7 g, 53.2 mmol) and iv (20 g, 53.2 mmol) in 1,4-dioxane:MeOH (300:180 mL) was added potassium phosphate (17 g, 79 mmol) at RT. The resulting mixture was degassed for 15-20 min by purging N2 followed by the addition of Pd(PPh3)4 (6.1 g, 5.32 mmol). The reaction mixture was again degassed for another 15-20 min and then heated up to 80° C. for 5 h. The reaction mixture was cooled to RT, diluted with EtOAc (500 mL) and passed through celite bed. The filtrate was evaporated and the crude residue was purified by chromatography on silica eluting with 1.5% MeOH:DCM to obtain Intermediate 7 (12 g, 41%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][C@H:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:16]([O:18]CC3C=CC=CC=3)=[O:17])[N:5](C(OCC3C=CC=CC=3)=O)[CH2:4]2)[CH2:2]1.[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:12]([O:11][C:9]([C@H:7]1[CH2:8][C:3]2([CH2:1][CH2:2]2)[CH2:4][NH:5][C@@H:6]1[C:16]([OH:18])=[O:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN(C(=O)OCc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1CC2(CC2)CN[C@@H]1C(=O)O
Yield: 99.6 %

Procedure:
5,6-dibenzyl 7-tert-butyl (6S,7S)-5-azaspiro[2.5]octane-5,6,7-tricarboxylate (2.0 g) was hydrogenated in methanol (100 mL) with 5% Pd—BaSO4 (750 mg) under a hydrogen atmosphere (hydrogen-balloon) at RT. The catalyst was removed by filtration. The filtrate was concentrated. The residue was dried under reduced pressure to produce (6S,7S)-7-(tert-butoxycarbonyl)-5-azaspiro[2.5]octane-6-carboxylic acid (1.06 g). MS (ESI): 256.1 (M+H+); 200.1 (M+H+-t-Bu).
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12]S(C)=O)[C:6]=1[NH2:7])([CH3:4])[CH3:3].CCCCCC>ClCCCl>[ClH:1].[CH:2]([C:5]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][Cl:1])[C:6]=1[NH2:7])([CH3:4])[CH3:3]
Reactant: CC(C)c1cccc(CS(C)=O)c1N
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCCl
Product: CC(C)c1cccc(CCl)c1N
Temperature: 50 °C
Yield: 96 %

Procedure:
Hydrogen chloride gas was introduced for 35 minutes into a solution of 7.74 g of 2-isopropyl-6-methylsulfinylmethylaniline [prepared as described in step (ii) above] in 80 ml of 1,2-dichloroethane warmed at 50° C., with the aid of a gas-inlet tube. The reaction mixture was then cooled to room temperature and 50 ml of hexane were added thereto. The crystals which precipitated were collected by filtration and washed with hexane to give 7.78 g (yield 96%) of the title aniline hydrochloride as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc([N+](=O)[O-])cc2Cl)cc1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
2-Chloro-4-nitroaniline (1.73 g (10.0 mmol)) was dissolved in 5.0 ml of pyridine. To this, p-toluenesulfonyl chloride (1.91 g (10.0 mmol)) was added with stirring at room temperature. After stirring for 18 hours at room temperature, water (50 ml) was added to the reaction mixture to bring about separation of crystals. The crystals were filtered, washed with water and then dissolved in an aqueous solution of sodium hydroxide. The resulting solution was washed with diethyl ether, and the water layer was made acidic again with hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.61 g (80%) of 2′-chloro-4′-nitro-p-toluenesulfonanilide as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.FC(F)(F)[C:13]([O:15][C:16](=O)C(F)(F)F)=[O:14].O>CN(C=O)C>[CH3:16][O:15][C:13]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1)=[O:14]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Fc1ccc2[nH]ccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 5-fluoroindole (5 g, 37.0 mmol) in DMF (40 mL) was treated at 0° C. with trifluoroacetic anhydride (6.1 mL, 42.6 mmol). After 30 min, the reaction was poured into water and the resulting precipitate collected by filtration, washed with water, then dried in vacuo. The solid was then dissolved in 10% aqueous NaOH (200 mL) and heated at reflux for 1 h. The reaction mixture was cooled to RT, washed with DCM and acidified with aqueous HCl. The resulting white precipitate was collected by filtration, washed with water, taken up in DCM, washed with water, dried (MgSO4) and evaporated in vacuo. The resulting material (5 g, 75%) was dissolved in methanol (80 mL) and treated with concentrated sulfuric acid (2 mL) then heated at reflux overnight. The reaction was cooled and the resulting precipitate collected, washed with water and concentrated in vacuo to give 5-fluoro-1H-indole-3-carboxylic acid methyl ester as a peach-coloured solid (4.5 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]=[C:21](Cl)[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]3[Cl:33])([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[OH:34][CH2:35][CH2:36][NH:37]C(=O)C(F)(F)F.C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[NH2:37][CH2:36][CH2:35][O:34][C:21]1[C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:19]([Cl:33])[C:18]2[C:23](=[CH:24][CH:25]=[C:16]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][CH:11]=3)[OH:9])[CH:17]=2)[N:22]=1
Reactant: O=C(NCCO)C(F)(F)F
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(-c3ccccc3)c(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(OCCN)c(-c3ccccc3)c(Cl)c2c1
Temperature: 25 °C

Procedure:
(4-Chlorophenyl)(2,4-dichloro-3-phenylquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.202 mmol, Example 65), N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (49 mg, 0.30 mmol), toluene (2 mL), and sodium hydride (60% dispersion in mineral oil, 32.3 mg, 0.808 mmol) were combined in a round bottom flask and heated at reflux for 48 hours under an N2 atmosphere. Analysis after overnight reaction showed only partial conversion, so additional N-(2-hydroxyethyl)-2,2,2-trifluoroacetamide (33 mg, 0.21 mmol) and sodium hydride (60% dispersion in mineral oil, 25 mg, 1.03 mmol) were added and the vessel was resealed and heated at reflux for an additional 48 hours. The reaction solution was then cooled to room temperature, diluted with EtOAc, transferred to a separatory funnel, and extracted with saturated, aqueous NH4Cl then saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified via reverse phase chromatography using acetonitrile with 0.05% trifluoroacetic acid in water as eluent. The fractions from the purification containing the desired product were transferred to a separatory funnel with EtOAc and extracted with a saturated, aqueous NaHCO3 solution. The aqueous layer was separated, extracted with EtOAc, then the combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound. MS (ESI): mass calcd. for C28H24Cl2N4O2, 518.1; m/z found, 519.2 [M+H]+; 1H NMR (600 MHz, CD3OD) δ ppm 8.17 (d, J=2.0 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.72 (dd, J=8.8, 2.1 Hz, 1H), 7.69 (s, 1H), 7.50-7.45 (m, 2H), 7.44-7.40 (m, 1H), 7.39-7.33 (m, 6H), 6.26 (s, 1H), 4.67-4.60 (m, 2H), 3.47 (s, 3H), 3.20 (t, J=5.3 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([NH2:5])([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([NH:16][N:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:28]([CH3:32])[C:29](O)=[O:30])=[N:18]2)=[O:15])=[CH:9][CH:8]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[C:2]([NH:5][C:29](=[O:30])[CH:28]([C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:17]([NH:16][C:14](=[O:15])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=2)[N:18]=1)[CH3:32])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C(=O)O)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C(=O)NC(C)(C)C)c1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 2-methylpropan-2-amine (34.1 mg, 0.467 mmol) in THF (5 mL), were added the product from Example 110 (150 mg, 0.389 mmol), triethylamine (0.163 mL, 1.17 mmol), and 1-propanephosphonic acid cyclic anhydride (50% in EtOAc, 0.463 mL, 0.778 mmol). The mixture was stirred at 70° C. for 16 hours, cooled, quenched with 1M NaHCO3 (10 mL), extracted with EtOAc (2×20 mL), dried (Na2SO4-d6), filtered, and concentrated. The residue was purified by chromatography (SiO2, 0-100% of 1/10 MeOH/EtOAc in hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.31 (d, J=7.8, 1H), 8.01-7.97 (m, 2H), 7.93 (s, 1H), 7.87 (ddd, J=8.2, 5.4, 3.0, 1H), 7.41 (s, 4H), 4.24 (q, J=6.8, 1H), 3.68 (s, 2H), 1.39 (d, J=6.9, 3H), 1.23 (s, 9H); MS (ESI+) M/Z 441 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[C:13]2[C:20]([CH3:21])=[CH:19][N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=2[N:15]=[CH:16][CH:17]=1>C(O)C.C1COCC1.[Pt-]=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]2[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[CH:19]=[C:20]([CH3:21])[C:13]=12
Reactant: Cc1cn(COCC[Si](C)(C)C)c2nccc(Nc3ccc([N+](=O)[O-])cc3F)c12
Agent: O=[Pt-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cn(COCC[Si](C)(C)C)c2nccc(Nc3ccc(N)cc3F)c12
Reaction time: 8 h

Procedure:
20 mg (50 μmol) of N-(2-fluoro-4-nitrophenyl)-3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-4-amine are dissolved in 8 ml of a mixture of ethanol/THF (1:1). 11 mg (50 μmol) of platinum(I) oxide are added, and the mixture is stirred under a hydrogen atmosphere at atmospheric pressure overnight. The suspension is then filtered through Celite, the Celite is washed with a little ethanol and the solvent is removed under reduced pressure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1>>[O:13]=[C:14]1[NH:33][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][C:22]([O:26][CH2:27][CH2:28][CH2:29][C:30]([N:10]4[CH2:11][CH2:12][N:7]([C:2]5[N:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[CH2:8][CH2:9]4)=[O:31])=[CH:23][C:24]=3[CH:25]=[C:16]2[NH:15]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Product: O=C(CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1)N1CCN(c2ncccn2)CC1

Procedure:
Reaction of N-(2-pyrimidinyl)piperazine and 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid (2 g) analogously to the procedure of Example 4 gave the title compound as the hydrated dihydrochloride salt; yield 3.67 g (100%), m.p. 184°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([NH:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH2:7]1.C(N(CC)C(C)C)(C)C.[CH2:31]([O:33][C:34](=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41])[CH3:32]>ClCCl>[CH2:31]([O:33][C:34](=[O:43])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:41])[N:12]([CH:9]1[CH2:10][CH2:11][N:6]([CH2:5][C:4]2[C:3]([O:2][CH3:1])=[CH:19][CH:18]=[CH:17][C:16]=2[O:20][CH3:21])[CH2:7][CH2:8]1)[CH:13]([CH3:15])[CH3:14])[CH3:32]
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: COc1cccc(OC)c1CN1CCC(NC(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(=O)N(C(C)C)C1CCN(Cc2c(OC)cccc2OC)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A solution of [1-(2,6-dimethoxybenzyl)piperidin-4-yl]isopropylamine (1.3 g, 4.6 mmol) and N,N-diisopropylethylamine (1.2 mL, 9.9 mmol) in dichloromethane (40 mL) was cooled to 0° C. under nitrogen. 6-Chlorocarbonylhexanoic acid ethyl ester (0.73 mL, 5.0 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 2 h and then at room temperature for an additional 2 h. The reaction mixture was then transferred to a separatory funnel and washed with NaHCO3 (2×) and brine (1×). The organic layer was then dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title intermediate as a yellow oil (2.2 g), which was used without further purification.