Azzindani/Open_Reaction_Data huggingface dataset:
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.[CH2:16]=[O:17].[OH-].[Na+]>C(O)C>[OH:17][CH2:16][N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1
Reactant: C=O
Reactant: c1ccc(-c2n[nH]c3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OCn1nc(-c2ccccc2)c2ccccc21
Yield: 77.6 %

Procedure:
3-Phenylindazole (9.71 g), paraformaldehyde (2.25 g) and 5% aqueous sodium hydroxide solution (1 ml) were added to ethanol (40 ml) and the mixture was heated under reflux for 3 hours. After cooling the reaction mixture, the precipitated crystals were recovered by filtration to obtain 8.7 g of 1-hydroxymethyl-3-phenylindazole having a melting point between 103°-105° C after recrystallization from ligroine.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=O)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH2:42])[CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][NH:42][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([C:21]3[CH:20]=[CH:19][C:18]4[N:14]([C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:32])[F:33])=[O:6])[CH:9]=5)[CH:15]=[N:16][C:17]=4[CH:22]=3)[CH:24]=2)[CH2:37][CH2:36]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Reactant: CN1CCC(CN)CC1
Product: CN1CCC(CNC(=O)c2cccc(-c3ccc4c(c3)ncn4-c3cccc(NC(=O)NCC(F)(F)F)c3)c2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 1 starting from 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)-phenyl]-1H-benzimidazol-5-yl}benzoic acid and 1-(1-methylpiperidin-4-yl)methanamine (Matrix Sci., Cat. No. 016352). LCMS (M+H)+: m/z=565.3.
Reaction SMILES: [CH:1]1([C:4]2[NH:12][C:11]3[C:10](=O)[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].[OH-].[Na+]>N1C=CC=CC=1>[CH:1]1([C:4]2[NH:12][C:11]3[C:10](=[S:19])[NH:9][C:8](=[S:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CCCn1c(=S)[nH]c(=O)c2[nH]c(C3CC3)nc21
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCn1c(=S)[nH]c(=S)c2[nH]c(C3CC3)nc21
Reaction time: 8 h
Yield: 54.6 %

Procedure:
In a 5 L 3-necked flask fitted with a mechanical stirrer and a condenser with a drying tube were placed 2.2 L of pyridine and 8-cyclopropyl-3-propyl-2-thio-xanthine (220 g, 0.88 mol). Phosphorus pentasulfide (236 g, 1.06 mol) was added and the mixture was heated under reflux for 5 hours and stored overnight at room temperature. The reaction mixture was cooled to 5-10° and 3 N aqueous sodium hydroxide (770 ml) was added over 1.5 hours with stirring. Stirring was continued for 30 minutes after removal of the cooling bath and the precipitated product was collected by suction filtration. The filter cake was washed successively with pyridine (300 ml) and four 300 ml portions of tetrahydrofuran. The solvents are evaporated in vacuo and the solid residue was stirred with water (750 ml), filtered and washed with water. The crude product was dissolved in 1.7 L of 1 N sodium hydroxide and stirred with 15 g of Darco G-60. The charcoal was filtered and the treatment was repeated with a fresh portion of charcoal. The solution was acidified to pH 1.5 with 6 N hydrochloric acid and the pale yellow precipitate was collected. The solid was dissolved again in 1.7 L of 1N sodium hydroxide and treated successively with two portions of charcoal as above. The solution was acidified and the precipitate was collected and washed with water. After drying to constant weight at 54° C. under vacuum, there was obtained 128 g (56%) of the title compound, mp over 245° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C>CS(C)=O>[F:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH2:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH2:16][CH:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)[CH2:40]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Reactant: Fc1ccc2[nH]cc(CC3CCCNC3)c2c1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCCC(Cc2c[nH]c4ccc(F)cc24)C1)O3

Procedure:
A solution of (2R)-4-bromobenzenesulfonic acid 8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl ester (0.090 g, 0.24 mmol), 5-fluoro-3-piperidin-3-ylmethyl-1H-indole (0.56 g, 0.24 mmol) and triethylamine (0.042 mL, 0.36 mmol) in dimethylsulfoxide (10 mL) was heated at 90° C. under nitrogen overnight. The reaction mixture was quenched with 1N sodium hydroxide and extracted with methylene chloride (3×50 mL). The organic layer was washed with water (3×50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum. The crude oil was column chromatographed on silica gel (5% methanol-75% ethyl acetate-20% hexane). The product-containing fractions were concentrated in vacuum to give 0.048 g (53%) of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate and collected as 0.037 g of a yellow solid, m.p. 68° C. (dec).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:3]2[C:4]3[CH:9]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][C:5]=3[N:1]=[CH:2]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2[nH]cnc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2ncn(-c3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 13 %

Procedure:
A suspension of methyl 1H-benzimidazole-5-carboxylate (10.4 g, 58.8 mmol), (4-methoxyphenyl)boronic acid (17.9 g, 118 mmol), copper(II) acetate (16.0 g, 88.2 mmol), pyridine (9.54 mL, 118 mmol) and molecular sieves 4A (24.0 g) in dichloromethane (240 mL) was stirred at room temperature for 6 hr. The reaction mixture was filtered, and the filtrate was washed with 5% aqueous ammonia and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/ethyl acetate=5/1) and recrystallized from hexane/ethyl acetate to give the title compound (2.15 g, yield 13%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[C:22]3[C:26]=2[C:25](=[O:27])[N:24]([CH3:28])[CH2:23]3)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:6][CH:7]=1.[CH2:35]=O.[OH-].[Na+]>ClC(Cl)C>[Cl:1][C:2]1[C:3]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:22]3[C:26]=2[C:25](=[O:27])[N:24]([CH3:28])[CH2:23]3)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[N:6][CH:7]=1
Reactant: C=O
Reactant: COc1ccccc1Nc1ncc(Cl)c(Nc2ccc(N3CCNCC3)c3c2C(=O)N(C)C3)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1ccccc1Nc1ncc(Cl)c(Nc2ccc(N3CCN(C)CC3)c3c2C(=O)N(C)C3)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 58.3 %

Procedure:
To a solution of 7-[5-chloro-2-(2-methoxy-phenylamino)-pyrimidin-4-ylamino]-2-methyl-4-piperazin-1-yl-2,3-dihydro-isoindol-1-one (2.0 g, 4.17 mmol) in dichloroethane (50 mL), formaldehyde (380 μL, 5.0 mmol) is added and the mixture is stirred at room temperature for 1.5 hours. After addition of triacetoxy sodium borohydride (1.06 g, 5.0 mmol), the mixture is stirred at room temperature for 1.5 hours. The mixture is poured into 1N sodium hydroxide and stirred at room temperature for 10 min, then extracted twice with dichloromethane. The organic layer is successively washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting solids are washed with methanol and ethyl acetate to give 7-[5-Chloro-2-(2-methoxy-phenylamino)-pyrimidin-4-ylamino]-2-methyl-4-(4-methyl-piperazin-1-yl)-2,3-dihydro-isoindol-1-one (1.2 g) as pale yellow solids in 58% yield. Rf=0.30 (MeOH/AcOEt=½). ESI-MS m/z: 494 [MH]+. 1H-NMR (400 MHz, CDCl3, δ, ppm): 2.38 (s, 3H), 2.66-2.57 (m, 4H), 3.09-3.07 (m, 4H), 3.21 (s, 3H), 3.92 (s, 3H), 4.37 (s, 2H), 6.92 (dd, 1H), 7.03-6.96 (m, 2H), 7.13 (d, 1H), 7.45 (s, 1H), 8.11 (s, 1H), 8.33 (dd, 1H), 8.67 (d, 1H), 10.5 (s, 1H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@H:3]([N:9]1[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][CH3:20])[C:10]1=[O:21])[CH2:2]2.[H][H].O>CO.[Pd]>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@H:3]([N:9]1[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][CH3:20])[C:10]1=[O:21])[CH2:2]2
Reactant: [H][H]
Reactant: CCc1cccc2c(=O)n([C@@H]3CN4CCC3CC4)ccc12
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCc1cccc2c1CCN([C@@H]1CN3CCC1CC3)C2=O
Yield: 112 %

Procedure:
(S)-2-(1-Azabicyclo[2.2.2]oct-3-yl)-5-ethyl-1(2H)-isoquinolinone (0.49 g, 1.5 mmol), from Example 2, was dissolved in methanol (10 ml) and reduced with hydrogen and 10% palladium on carbon at 50 psi for 5 hours. Filtration to remove the catalyst and evaporation of the methanol gave (S)-2-(1-azabicyclo[2.2.2]oct-3-yl)-5-ethyl-3,4-dihydro-1(2H)-isoquinolinone (0.48 g, 1.68 mmol), m.p. >290° C., [α]D25 -40.3° (c=0.64 H2O ).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].C([O-])(O)=O.[Na+].[I:15]I>O>[Cl:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([NH2:6])=[C:7]([I:15])[CH:8]=1
Reactant: II
Reactant: Nc1ccc(Cl)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1cc(F)c(Cl)cc1I
Temperature: 0 °C
Reaction time: 18 h
Yield: 101846.3 %

Procedure:
To 4-chloro-3-fluoroaniline (25 g, 0.17 mmol) in 250 mL of H2O was added NaHCO3 (21.6 g, 0.25 mmol). After cooling to 0° C., iodine (43.5 g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8 g of iodine was added and the reaction was stirred overnight. The reaction was extracted with DCM (4×250 mL), the combined organics were washed with sodium thiosulfate solution (2×250 mL) and brine (2×250 mL) and dried (Na2SO4). Purification by silica gel chromatography gave 47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H)+.
Reaction SMILES: C(ON=O)(C)(C)C.Br[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12].[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)N)([O-:17])=[O:16].NC1C=CC=CC=1>CC#N>[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])([O-:17])=[O:16]
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: C=C(CBr)C(=O)O
Agent: CC(C)(C)ON=O
Solvent: Nc1ccccc1
Solvent: CC#N
Product: C=C(Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O
Temperature: 17.5 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and 2-(bromomethyl)acrylic acid (7.42 g, 45.0 mmol) in CH3CN (10 ml), 3,5-dinitroaniline (549 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 15-20° C. At the end of the addition of the aniline extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture. After heating to 35° C. for 5 minutes, the mixture was stirred at room temperature for one hour. The volatile material in the reaction mixture was then removed at reduced pressure. The remaining crystalline residue was washed with heptane (5×50 ml) to remove unreacted 2-(bromomethyl)acrylic acid. Column chromatography (heptane-ethyl acetate-methanol-acetic acid 5:4:1:0.04) of the remaining crude product followed by crystallization from toluene gave 450 mg (60%) of 2-(3,5-dinitrobenzyl)acrylic acid as yellow needles. 1H NMR (CDCl3, 300 MHz) δ 8.93, (t, 1H, J=2.1 Hz), 8.43, (d, 2H, J=2.1 Hz), 6.56, (s, 1H), 5.93, (m, 1H), 3.85, (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Br[CH2:12][CH:13]1[CH2:18][CH2:17][Si:16]([CH2:25][CH2:26][CH2:27][CH:28]([F:30])[CH3:29])(C2C=CC=CC=2)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]([O:10][CH2:12][C@H:13]2[CH2:14][CH2:15][Si@H:16]([CH2:25][CH2:26][CH2:27][CH:28]([F:30])[CH3:29])[CH2:17][CH2:18]2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Oc1cc(F)c(F)c(F)c1
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC(CBr)CC1
Product: CC(F)CCC[Si@H]1CC[C@H](COc2cc(F)c(F)c(F)c2)CC1

Procedure:
The general procedure of Example 9 was repeated using 3,4,5-trifluorophenol and 4-bromomethyl-1-(4-fluoropentyl)-1-phenyl-1-silacyclohexane, thereby obtaining the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41]N)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:41][C:38]3[C:39]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:28])[CH3:29])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:40][C:35]([O:34][CH3:33])=[CH:36][CH:37]=3)=[CH:6][CH:7]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: COc1ccc2[nH]c(-c3ccc(Cl)cc3)c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c2c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-methoxyphenylhydrazine hydrochloride: ESMS m/e: 544.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:11])[CH2:7][C:8](=O)[CH3:9].C([O-])(=O)C.[NH4+:16]>C1(C)C=CC=CC=1>[NH2:16][C:8]([CH3:9])=[CH:7][C:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)=[O:11]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)c1ccco1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(N)=CC(=O)c1ccco1
Yield: 48.9 %

Procedure:
The intermediate 3-amino-1-(2-furanyl)-2-buten-1-one was prepared as follows: A mixture containing 165 g of 1-(2-furanyl)-1,3-butanedione, 700 ml of toluene and 200 g of ammonium acetate was azeotroped for six hours, cooled and concentrated to dryness in vacuo. The residue was dissolved in isopropyl alcohol, the solution treated with decolorizing charcoal and filtered, and the filtrate concentrated to remove the solvent. The remaining residue was recrystallized from ether-ethanol and dried at room temperature to yield 80.2 g of 3-amino-1-(2-furanyl)-2-buten-1-one, m.p. 128°-130° C. Another 33.4 g of the product, m.p. 128°-130° C. was collected by concentrating the mother liquor and extracting the product with ether.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:17](=[O:25])[C:16]3=[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=4)[CH:27]=[CH:28][N:15]3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:17](=[O:25])[C:16]3=[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=4)[CH:27]=[CH:28][N:15]3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: COc1cccc(Cc2ccn3nc([C@H](C)Nc4ncnc(N)c4C#N)n(-c4ccccc4)c(=O)c23)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nn2ccc(Cc3cccc(O)c3)c2c(=O)n1-c1ccccc1
Yield: 39 %

Procedure:
(S)-4-Amino-6-((1-(5-(3-methoxybenzyl)-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile (72 mg, 0.15 mmol) was treated with boron tribromide (1M in dichloromethane, 580 μl, 0.58 mmol) with dichloromethane as a solvent according to the method described in Example 23. The residue was purified by reverse phase using SP1® Purification System to give 27 mg (39% yield) as a solid. Purity 98%.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[O:20]1[C:24]2([CH2:28][CH2:27][NH:26][CH2:25]2)[O:23][CH2:22][CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:26]4[CH2:27][CH2:28][C:24]5([O:23][CH2:22][CH2:21][O:20]5)[CH2:25]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1CC2(CN1)OCCO2
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC4(C3)OCCO4)c(F)cc2c1=O

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is reacted analogously to Example 11 with 1,4-dioxa-7-azaspiro[4.4]nonane to give 1-cyclopropyl-7-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid of melting point 229°-230°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20]N(C)C)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][C:33]1[CH2:38][C:37]([CH3:40])([CH3:39])[CH2:36][C:35](=[O:41])[CH:34]=1>C(O)(=O)C>[C:1]([O:5][C:6](=[O:31])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:20][C:34]4[C:35](=[O:41])[CH2:36][C:37]([CH3:40])([CH3:39])[CH2:38][C:33]=4[N:32]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: CC1(C)CC(=O)C=C(N)C1
Solvent: CC(=O)O
Product: CC1(C)CC(=O)c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2C1
Temperature: 100 °C
Yield: 40.3 %

Procedure:
To a solution of tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (166 mg, 0.40 mmol) in acetic acid (1 mL) was added molecular sieves (10 mg) and 3-amino-5,5-dimethylcyclohex-2-enone (82 mg, 0.59 mmol) under nitrogen. The resulting mixture was heated at 100° C. for 2 h. After cooled down to room temperature, the mixture was partitioned between water (10 mL) and dichloromethane (10 mL). The layers were separated and the aqueous phase extracted into dichloromethane (2×10 mL). The combined organic phases were washed with saturated NaHCO3 solution (20 mL), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 20% EtOAc in hexane) to give the title compound (80 mg, 41%). 1H NMR (500 MHz, CDCl3): 8.27 (1H, s), 7.37 (2H, d), 7.30 (2H, d), 7.25-7.24 (3H, m), 7.19-7.17 (2H, m), 5.06 (1H, br s), 3.13 (2H, s), 2.59 (2H, s), 2.55-2.25 (4H, m), 2.09-2.01 (1H, m), 1.82-1.77 (1H, m), 1.44-1.15 (9H, br), 1.17 (6H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([OH:10])(=O)=[O:8])[CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([Cl:12])(=[O:10])=[O:8])[CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)(O)c1cccnc1
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyridine-3-sulfonic acid (125 g, 0.78 m) was placed in a 1 L, 3-necked flask equipped with mechanical stirrer, reflux condenser, thermometer and nitrogen inlet. Next, the phosphorus pentachloride (250 g, 1.19 m, 1.5 eq) was added, followed immediately by the phosphorus oxychloride (330 ml, 3.8 m, 4.5 eq). The contents of flask were initially stirred at ambient temperature for 30 min, then brought slowly to gentle reflux (internal temp. approx. 110° C.) over the next hour, kept at this temperature for approx. 3.5 hr then allowed over the next 12 hr to cool back to ambient temperature. Gas evolution was observed during this time. The volatiles were stripped under reduced pressure (at 12 mmHg/40° C.) and yellow semi-solid residue was diluted with DCM (1 L). The slurry was poured slowly into the stirred, ice-cold sat. aq. bicarbonate, maintaining pH=7. Gas evolution was observed. The organic layer was separated and aqueous layer was back-extracted with DCM. The combined extracts were washed with cold sat. aq. bicarbonate, brine and dried with magnesium sulfate. The solids were filtered off and filtrate evaporated, leaving pyridine-3-sulfonyl chloride as a pale yellow, oily liquid, 123 g (93% pure; 88% theory). 1H-NMR, CDCl3, (δ): 9.26 (d, 1H), 8.98 (dd, 1H), 8.34 (m, 1H), 7.62 (m, 1H). 13C-NMR, CDCl3, (δ): 155.3, 147.4, 140.9, 134.6, 124.2.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:12][CH2:13][C:14]#[C:15][OH:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OC#CCCc1ccnc2cc(Cl)ccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: OCCCCc1ccnc2cc(Cl)ccc12
Reaction time: 2 h
Yield: 49.1 %

Procedure:
4-(7-chloroquinolin-4-yl)butyn-1-ol (1 g) was dissolved in ethanol (25 mL) in a Parr hydrogenation bottle and platinum (IV) oxide [Adams' Catalyst] (100 mg) was added. The Parr bottle was placed on a Parr hydrogenation apparatus and the solution hydrogenated at 50 psi for 2 hours after which time the starting material had been judged to be consumed by TLC. The spent catalyst was removed by filtration through a Celite pad and the pad carefully washed with more ethanol. The combined filtrates were evaporated in vacuo and the residue purified by flash chromatography on silica gel (ethyl acetate; then ethyl acetate:methanol, 95:5) to give the title compound (500 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][CH2:19][C:20]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1([CH:24]=[O:25])[CH2:21][CH2:22][CH2:23]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CO)CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCC1(C=O)CCC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
To a round bottom flask was added DCM (5.0 mL) and oxalyl chloride (2.0 M solution in DCM, 1.36 mL, 2.71 mmol). The reaction mixture was cooled to about −78° C. To the solution was added a solution of DMSO (0.385 mL, 5.42 mmol) in DCM (1.0 mL). The mixture was stirred for about 15 min at about −78° C. and then a solution of (1-((tert-butyldimethylsilyloxy)methyl)cyclobutyl)methanol (0.500 g, 2.17 mmol, prepared using General Procedure AL with diethyl cyclobutane-1,1-dicarboxylate [Fluka], General Procedure AK with tert-butylchlorodimethylsilane) in DCM (1.0 mL) was added. The reaction mixture was allowed to stir for about 15 min and then TEA (1.82 mL, 13.0 mmol) was added. The reaction mixture was allowed to stir for about 15 min and then warmed to ambient temperature. The reaction mixture was quenched with water (25 mL) and was extracted with DCM (3×25 mL). The organics were combined, dried with MgSO4, filtered and concentrated in vacuo to give the title compound as a colorless oil (0.486 g, 98%): 1H-NMR (DMSO-d6) δ 9.71 (s, 1H), 3.87 (s, 2H), 2.27 (m, 2H), 1.93 (m, 4H), 0.90 (s, 9H), 0.08 (s, 6H).