Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]#[C:24][Si](C)(C)C)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:29]([NH2:31])=[O:30])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]#[CH:24])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:29]([NH2:31])=[O:30])=[CH:12][N:11]=2)[C:5]([F:8])([F:6])[F:7])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Product: C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-[(trimethylsilyl)ethynyl]-5H-pyrido[4,3-b]indole-4-carboxamide (0.15 g, 0.33 mmol) in MeOH (3.3 mL) was added potassium carbonate (0.055 g, 0.40 mmol). The reaction mixture was left to stir at room temperature for 16 h, diluted with EtOAc, washed with water and brine, dried (sodium sulfate), and concentrated to give the title compound. LRMS (APCI) calc'd for (C19H15F3N4O) [M+H]+, 373.1. found 373.1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][NH:11][C:12](=[O:15])[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:21](Br)[C:22]#[CH:23].O>O1CCCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=2)[CH2:10][N:11]([CH2:23][C:22]#[CH:21])[C:12](=[O:15])[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)NCc1cccc(-c2ccccc2)c1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCN(Cc1cccc(-c2ccccc2)c1)C(=O)OC
Reaction time: 8 h
Yield: 66.6 %

Procedure:
0.70 g of methyl N-(3-phenylbenzyl)carbamate in tetrahydrofuran (20 ml) was stirred together with 0.15 g of 60% sodium hydride at room temperature for 30 minutes. 0.52 g of propargyl bromide was added dropwise at room temperature, and the resulting solution was stirred overnight. After the reaction, the reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 0.54 g of methyl N-(3-phenylbenzyl)N-(2-propynyl)carbamate as a yellow transparent viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][NH2:25])=[CH:15]1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:15]4[NH:14][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:23][CH2:24][NH:25]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=CC1(c2ccc(Cl)cc2)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(C2(C3NCCc4c3[nH]c3ccccc43)CCC2)cc1
Temperature: 25 °C

Procedure:
1-(4-Chlorophenyl)cyclobutanecarbaldehyde (30 mg, 0.154 mmol) and 2-(1H-indol-3-yl)ethanamine (27.7 mg, 0.17 mmol) were dissolved in dichloromethane (3 mL). Trifluoroacetic acid (88 mg, 0.771 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature over night. The 5% NaHCO3 solution was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed successively with 5% NaHCO3 solution and saturated sodium chloride solution, dried (MgSO4) and concentrated in vacuo. Yield: 36 mg (oil, 0.107 mmol, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2([C:18]#N)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]2)=[C:4](I)[CH:3]=1.[Li]CCCC.C1C[O:31]CC1>>[Br:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][C:7]3([CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]3)[C:18]2=[O:31])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C#N)(Cc2ccc(Br)cc2I)C1
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: CC(C)(C)OC(=O)N1CC2(Cc3ccc(Br)cc3C2=O)C1
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of tert-butyl 3-(4-bromo-2-iodobenzyl)-3-cyanoazetidine-1-carboxylate (4.2876 g, 8.99 mmol) in THF (120 mL) was added n-BuLi (2.5 Min hexane, 3.8 mL, 9.5 mmol) at −78° C. dropwise over 10 min under nitrogen. After 1 h, the reaction mixture was quenched with saturated NH4Cl, diluted with CH2Cl2, and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1.7020 g (54%) of tert-butyl 6′-bromo-1′-oxo-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1-carboxylate as a solid. LC-MS tR=1.90 min in 3 min chromatography, m/z 352, 354 (MH+), 337, 339 (MH+-15), 296, 298 (MH+-56); 1H NMR (400 MHz, CDCl3) δ 7.91 (m, 1H), 7.74-7.71 (m, 1H), 7.35 (d, J=7.9 Hz, 1H), 4.23 (d, J=8.2 Hz, 2H), 3.88 (d, J=8.2 Hz, 2H), 3.40 (s, 2H), 1.46 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 204.38, 156.03, 150.44, 138.17, 137.24, 127.88, 127.29, 122.19, 80.05, 57.88, 44.70, 39.67, 28.35.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][C:25]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][C:25]3([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Reactant: NCC1(O)CCCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1NCC1(O)CCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (54.42 g, 188.6 mmol) in chloroform (820 mL) was cooled to 0° C., and triethylamine (105 mL, 755 mmol) was added. A solution of 1-(aminomethyl)cyclopentanol (28.25 g, 245.2 mmol) in chloroform (272 mL) was added slowly over a period of 15 minutes. The reaction was allowed to warm to room temperature and stirred for 30 minutes. The solution was washed sequentially with water (500 mL) and saturated aqueous sodium bicarbonate (750 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 1-{[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]methyl}cyclopentanol.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccnc(Cl)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light yellow solid (72 mg, 86%), MS (ISP) m/z=337.3 [(M+H)+], mp 286.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([C:7]1[CH:8]=[C:9]([CH:15]=[C:16]([CH2:18]O)[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:6])[CH2:2][CH3:3].P(Br)(Br)[Br:24]>ClCCl>[Br:24][CH2:18][C:16]1[CH:15]=[C:9]([CH:8]=[C:7]([C:5]([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])=[O:6])[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)OCC)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(CBr)cc(C(=O)OCC)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate (1.5 g) and phosphorous tribromide (0.95 mL) is stirred in dichloromethane (10 mL) and heated at 50 degrees C. for 4 hours and then cooled and partitioned between dichloromethane and water. The organic phase is separated and washed with aqueous sodium bicarbonate and then dried over magnesium sulfate and taken to dryness to give ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate, high resolution MS MH+=370.1020. Ethyl 3-(bromomethyl)-5-[(dipropylamino)carbonyl]benzoate (1.4 g) and sodium cyanide (0.2 g) are stirred in dry DMSO (25 mL) at 20-25 degrees C. for 3.5 hours and the mixture is then partitioned between ethyl acetate, water and saline. The organic layer is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate. Ethyl 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoate (0.6 g) is hydrolyzed with lithium hydroxide monohydrate (0.1 g) in ethanol and water at 20-25 degrees C. overnight and then added to water (50 mL). The pH is adjusted to 4 using concentrated hydrochloric acid and the mixture is partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate and taken to dryness under reduced pressure to give 3-(cyanomethyl)-5-[(dipropylamino)carbonyl]benzoic acid, MS M+H=287.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[N:28]=[CH:27][N:26]=[C:25]2[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH3:50])=[CH:44]2.C(=O)([O-])O.[Na+]>C(Cl)Cl.CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([CH2:4][CH2:3][O:2][CH3:1])[CH2:36][CH2:35]1)[N:28]=[CH:27][N:26]=[C:25]2[O:40][C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[NH:46][C:45]([CH3:50])=[CH:44]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CCNCC1
Reactant: COCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COCCN1CCC(COc2cc3ncnc(Oc4ccc5[nH]c(C)cc5c4)c3cc2OC)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
Methoxyacetaldehyde (368 mg, 3.47 mol) (freshly distilled) followed by sodium triacetoxyborohydride (552 mg, 2.6 mol) were added to a solution of 6-methoxy-4-(2-methylindol-5-yloxy)-7-(piperidin-4-ylmethoxy)quinazoline (726 mg, 1.74 mmol), (prepared as described in Example 70), in a mixture of methylene chloride (15 ml) and methanol (15 ml). After stirring for 1.5 hours at ambient temperature, saturated sodium hydrogen carbonate was added. The volatiles were removed under vacuum and the residue was partitioned between methylene chloride and water. The organic layer, was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (80/20). After removal of the solvent, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 6-methoxy-7-(1-(2-methoxyethyl)piperidin-4-ylmethoxy)-4-(2-methylindol-5-yloxy)quinazoline (392 mg, 47%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH3:10][O:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18][NH:1][C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(C=O)cn1
Reactant: Nc1ncc(C=O)cn1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2ncc(C=O)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a round bottom flask, 2-amino-pyrimidine-5-carbaldehyde (31, 0.750 g, 6.09 mmol), 6-methoxy-pyridine-3-carbaldehyde (29, 1.67 g, 12.2 mmol), trifluoroacetic acid (2.5 mL, 32.0 mmol), and triethylsilane (5.00 mL, 31.3 mmol) were combined with 10 mL of acetonitrile. The reaction was stirred at room temperature overnight, then concentrated under vacuum and combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel flash column chromatography, eluting with 15-100% ethyl acetate in hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>C(OCC)(=O)C>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-hydroxy-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.68 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.65 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) with the following workup: the reaction mixture was diluted with ethyl acetate, the resulting solution washed with 1N NaOH (2 ml), the aqueous layer extracted three times with ethyl acetate, the combined organic extracts washed with 1N HCl, dried and concentrated. The residue was purified by chromatography on silica gel eluted with 1-16% ethanol in dichloromethane. Yield, 150 mg, 52%; HPLC (60/40) 3.53 minutes (99%); PBMS 442/444 (MH+, 100%);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:12]([O:25][CH3:26])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[C:5]2[CH3:33].[CH3:34][NH2:35]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C@@H:11]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:12]([O:25][CH3:26])[CH2:13][NH:35][CH3:34])[CH:6]=[C:5]2[CH3:33]
Reactant: CN
Reactant: COC(COS(=O)(=O)c1ccc(C)cc1)C(c1ccccc1)n1cc(C)c2cc(Cl)ccc21
Solvent: CO
Product: CNC[C@@H](OC)[C@H](c1ccccc1)n1cc(C)c2cc(Cl)ccc21
Reaction time: 1 h

Procedure:
A mixture of (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-hydroxy-3-phenyl-propyl ester (Intermediate in EXAMPLE 119, step 6, 0.52 g, 1.1 mmol), trifluoro-methanesulfonic acid methyl ester (0.6 mL, 5.5 mmol), and 2,6-di-tert-butyl-4-methyl-pyridine (1.1 g, 5.5 mmol) was heated at reflux in dichloromethane (20 mL) for 2 hours. The reaction was partitioned between ethyl acetate (25 mL) and a 1N aqueous solution of hydrochloric acid (25 mL). The organics were separated and washed with a saturated aqueous solution of sodium bicarbonate (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified via flash column chromatography (silica, 20% ethyl acetate in hexane) to give (2S,3S)-toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester. To a solution of toluene-4-sulfonic acid 3-(5-chloro-3-methyl-indol-1-yl)-2-methoxy-3-phenyl-propyl ester (0.13 g, 0.27 mmol) in methanol (10 mL) was added a 2N solution of methylamine in methanol (1.4 mL, 2.7 mmol) and the reaction heated in a sealed tube for 12 hours. Upon completion, the reaction was partitioned between a saturated aqueous solution sodium bicarbonate (25 mL) and dichloromethane (25 mL). The organics were separated and removed in vacuo. The residue was taken up in diethyl ether (25 mL) and washed with a 1 N aqueous solution of hydrochloric acid (25 mL). The aqueous layer was basified to pH 8 with a saturated aqueous solution of sodium bicarbonate (50 mL). The product was extracted with diethyl ether (25 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The free base was dissolved in a minimum amount of ethanol and treated with a 4N solution of hydrochloric acid in dioxane and stirred for 1 hour s. The ethanol was removed in vacuo to give [(2R,3S)-3-(5-chloro-3-methyl-1H-indol-1-yl)-2-methoxy-3-phenylpropyl]methylamine as a yellow oil. MS (ESI) m/z 343
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[F:15][C:16]([F:40])([F:39])[C:17]1[N:21]2[N:22]=[C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:24]=[CH:25][C:20]2=[N:19][N:18]=1.[Br:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:41][CH2:42][CH2:43][O:38][C:35]1[CH:36]=[CH:37][C:32]([N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:24]=[CH:25][C:20]4[N:21]([C:17]([C:16]([F:15])([F:39])[F:40])=[N:18][N:19]=4)[N:22]=3)[CH2:31][CH2:30]2)=[CH:33][CH:34]=1
Reactant: Oc1ccc(N2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1nnc2ccc(N3CCN(c4ccc(OCCBr)cc4)CC3)nn12
Temperature: 20 °C
Reaction time: 16 h
Yield: 19.7 %

Procedure:
DIAD (1.625 mL, 8.25 mmol) was added to 4-[4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]phenol (obtained as described in Example 514, preparation of starting materials) (3.01 g, 8.25 mmol), 2-bromoethanol (0.645 mL, 9.08 mmol) and triphenylphosphine (2.165 g, 8.25 mmol) in THF (150 mL) at 20° C. under nitrogen. The resulting solution was stirred at 20° C. for 16 hours. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM to afford 6-[4-[4-(2-bromoethoxy)phenyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.765 g, 19.67%) as a pale yellow solid.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:27])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH2:26])=[C:9]2[CH2:28][N:29]([S:33]([C:36]3[CH:41]=[C:40]([F:42])[CH:39]=[C:38]([F:43])[CH:37]=3)(=[O:35])=[O:34])[C:30]([CH3:32])([CH3:31])[C:8]2=[N:7]1)=O)C.[CH:44]1([C:48](Cl)=[O:49])[CH2:47][CH2:46][CH2:45]1>ClCCl.C(N(CC)C(C)C)(C)C>[CH:44]1([C:48]([NH:26][C:14]2[CH:15]=[C:16]([N:19]3[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]3)[CH:17]=[CH:18][C:13]=2[C:12]([NH:11][C:10]2[C:9]3[CH2:28][N:29]([S:33]([C:36]4[CH:37]=[C:38]([F:43])[CH:39]=[C:40]([F:42])[CH:41]=4)(=[O:34])=[O:35])[C:30]([CH3:32])([CH3:31])[C:8]=3[NH:7][N:6]=2)=[O:27])=[O:49])[CH2:47][CH2:46][CH2:45]1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCN(C)CC3)cc1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4c3CN(S(=O)(=O)c3cc(F)cc(F)c3)C4(C)C)c(NC(=O)C3CCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
To a solution of 3-[2-amino-4-(4-methyl-piperazin-1-yl)-benzoylamino]-5-(3,5-difluoro-benzenesulfonyl)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (105 mg, 0.17 mmol) in dichloromethane (5 mL) and N,N-diisopropylethylamine (1 mL), cyclobutanecarbonyl chloride (28.5 microL, 0.25 mmol) was added and the reaction mixture stirred at room temperature for 2 hours. The mixture was then diluted with dichloromethane (30 mL), washed with water (30 mL), dried over sodium sulphate and evaporated to dryness. The crude oil was then treated with MeOH (5 mL) and triethylamine (3 mL) and stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH-30% NH4OH 100:10:1 as the eluant, affording the title compound as white solid (21 mg).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[S:30]1[C:39]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[S:30]1[C:39]2[CH2:38][CH2:37][N:36]([C:27]([C:23]3[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]4[CH:17]=[C:18]5[C:13](=[CH:14][CH:15]=4)[CH2:12][C:4]4([C:5]6[C:6](=[N:7][CH:8]=[CH:9][CH:10]=6)[NH:11][C:3]4=[O:2])[CH2:19]5)[CH:22]=3)=[O:29])[CH2:35][CH2:34][C:33]=2[N:32]=[CH:31]1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Reactant: c1nc2c(s1)CCNCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1)N1CCc2ncsc2CC1

Procedure:
86 mg (0.21 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 37 mg (0.24 mmol) 5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine, 0.13 mL (0.72 mmol) DIPEA and 77 mg (0.24 mmol) TBTU in 1.0 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])[CH:6]=1>C(O)(=O)C>[N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([C:15]([C:17]2[CH:22]=[C:21]([N+:1]([O-:4])=[O:2])[C:20]([OH:23])=[C:19]([O:24][CH3:25])[CH:18]=2)=[O:16])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2cnc3ccccc3c2)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cnc3ccccc3c2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 1.91 ml of 65 percent nitric acid in 20 ml of glacial acetic acid is added dropwise to a solution of 5.5 g of 4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone in 300 ml of glacial acetic acid at 150° and the mixture is then stirred at this temperature for an additional 2 hours. The mixture is then poured into ice-water and extracted three times with 300 ml of ethyl acetate each time. The organic phase is washed five times with 100 ml of water each time, dried over sodium sulfate and evaporated. After treatment of the residue with ethyl acetate, there is obtained 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone in the form of yellow crystals of m.p. 220°-221° (dec.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.Cl[Sn](Cl)(Cl)Cl.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:34])[O:28][N:27]=2)=[CH:22][CH:21]=1.[N+](C)([O-])=O>C(Cl)Cl>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:31]([C:30]3[C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)=[N:27][O:28][C:29]=3[CH3:34])=[O:32])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1ccc2c(C(=O)c3c(-c4ccc(F)cc4)noc3C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.5 %

Procedure:
To a stirred solution of 1.75 g (10 mmol) methyl indole-6-carboxylate (commercially available) in 15 mL of dry CH2Cl2 under argon at 0° C. was added 1.41 mL (12 mmol) of SnCl4 in one portion. After removing the ice-bath, the mixture was stirred for 40 min at room temperature and then 2.39 g (10 mmol) of 3-(4-fluoro-phenyl)-5-methyl-isoxazole-4-carboxylic acid chloride (Prepared from the corresponding acid according to: J. Agric. Food Chem. 1995, 43, 219-228.) in 5 mL of CH2Cl2 was added at 0° C. followed by the addition of 15 mL of nitromethane in one portion. The mixture was stirred for 15 minutes at 0° C., after which 50 mL of ice-water was added to quench the reaction. The organic phase was separated and the aqueous solution was extracted with CH2Cl2 (2×20 mL). The combined extracts were washed with brine (30 mL), dried over Na2SO4, and evaporated to give 3.5 g of crude product (purity ˜30%, LCMS) as brown semi-solid. The crude product was further washed with ethyl acetate to give 0.85 g of the title compound in 23% yield as a light-yellow powder. (m/e): 379.2 (MH+; 100%).