Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][N:7]1[C:11](=[O:12])[C:10](=[CH:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[NH:9][C:8]1=[O:23].C([Li])CCC.[CH2:38](Br)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:38]([N:9]1[C:10](=[CH:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[C:11](=[O:12])[N:7]([CH2:6][C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=2)[C:8]1=[O:23])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: BrCc1ccccc1
Reactant: O=C1NC(=Cc2c[nH]c3ccccc23)C(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1C(=Cc2c[nH]c3ccccc23)N(Cc2ccccc2)C(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of the compound of Example 2 (0.5 g) in dry tetrahydrofuran (20 ml) was cooled to -78° C. and n-butyl lithium (0.72 ml of a 1.6M solution in hexanes) was added with stirring. After 15 minutes benzyl bromide (0.14 ml) was added. The solution was allowed to warm to room temperature then heated to reflux for 3 hours, cooled and poured into saturated ammonium chloride solution (20 ml). This mixture was extracted with ethyl acetate and the organic layers dried (MgSO4). The residue was purified by chromatography on silica gel eluting with ethyl acetate-petroleum ether (1:3) to give the title compound, mp 154°-156° C.; found: C, 61.66; H, 4.05; N, 7.64; C28H21F6N3O2 requires: C, 61.65; H, 3.88; N, 7.70.
Reaction SMILES: [F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@H:7]([C:9](=[O:16])[CH2:10][C:11](OCC)=[O:12])[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18].[OH-].[Na+].[NH2:24]O.Cl>CO.O.C(Cl)Cl>[F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@H:7]([C:9]2[O:16][NH:24][C:11](=[O:12])[CH:10]=2)[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](C(F)F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C(F)F
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 66.9 %

Procedure:
Trans-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (203 mg, 0.66 mmol) (from example 87, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (26.4 mg, 0.66 mmol) dissolved in water (0.300 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.040 mL, 0.66 mmol) was added. The resulting solution was stirred at −40° C. for 2 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (3.41 mL, 20.48 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 15 minutes with a flow of 19 mL/min. Trans-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (122 mg, 67%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.35-1.65 (m, 1H), 1.68-1.82 (m, 1H), 1.87-2.12 (m, 1H), 2.30-2.45 (m, 1H), 2.70-3.22 (m, 2H), 3.74 (s, 3H), 4.10-4.74 (m, 2H), 5.69 (s, 1H), 5.75-6.09 (m, 1H). MS m/z 275 (M−H)−
Reaction SMILES: [C:1](C1NC=CN=1)(C1NC=CN=1)=S.[NH2:13][C:14]1[CH:19]=[N:18][CH:17]=[CH:16][N:15]=1.[NH:20]([C:22](=[O:43])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:34][CH2:33]2)=[CH:28][CH:27]=1)=[O:24])[NH2:21].CCN=C=NCCCN(C)C>CC(N(C)C)=O.O>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[NH:13][C:1]1[O:43][C:22]([C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C@H:32]3[CH2:33][CH2:34][C@H:35]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH2:36][CH2:37]3)=[CH:30][CH:31]=2)=[O:24])=[N:20][N:21]=1
Reactant: Nc1cnccn1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)C(=O)NN)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)c3nnc(Nc4cnccn4)o3)cc2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Thiocarbonyl diimidazole (179 mg, 1.00 mmol) was added in one portion to a solution of aminopyrazine (96 mg, 1.00 mmol) in DMA (5 mL) and the solution was stirred at room temperature for 6 h. Methyl [trans-4-(4-{[hydrazino(oxo)acetyl]amino}phenyl)cyclohexyl]-acetate (Intermediate 43, 267 mg, 0.80 mmol) was added in one portion and the reaction mixture was stirred at room temperature for 20 h and then heated at 80° C. for 10 minutes in the microwave. The solution was cooled to room temperature and EDCI (192 mg, 1.00 mmol) was added in one portion and the reaction mixture was heated to 90° C. for 15 minutes in the microwave. The reaction mixture was cooled to room temperature and poured into water (200 mL). The mixture was filtered and the resulting solid was recrystallised (CH3CN) to give the title compound as an off white solid (35 mg, 8%); 1H NMR δ 1.15 (2H, m), 1.45-1.48 (2H, m), 1.79 (6H, m), 2.26 (2H, d), 2.45-2.49 (1H, m), 3.61 (3H, s), 7.23-7.25 (2H, d), 7.69-7.71 (2H, d), 8.36 (1H, d), 8.42 (1H, t), 9.19 (1H, s), 11.01 (1H, s); MS m/e MH+ 437.
Reaction SMILES: C(Cl)(Cl)Cl.[CH3:5][OH:6].[O:7]1[CH2:12][CH2:11][O:10]CC1>O.Cl>[O:6]=[CH:5][C@H:12]([C@H:11]([C@H:12]([CH2:11][OH:10])[OH:7])[OH:10])[OH:7]
Reactant: C1COCCO1
Reactant: CO
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C[C@@H](O)[C@@H](O)[C@@H](O)CO
Temperature: 40 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
1-O-benzoyl-2,3-O-isopropylidene-L-ribonofuranoate (10 g) prepared in Example 6 was dissolved in a solvent mixture of methanol (30 ml) and 1.0N aqueous sodium-hydroxide solution (10 ml) and then reacted for about 3 hours. After TLC revealed the completion of reaction, the reaction solution was distilled under reduced pressure, water (10 ml) was added, and the reaction mixture was extracted two to three times with ethyl acetate. The extract was dried over magnesium sulfate and distilled under reduced pressure to give 2,3-isopropylidene-L-ribose (6.0 g). The compound thus obtained was dissolved in a solvent mixture of dioxane (12 ml) and water (12 ml), 1.0N hydrochloric acid solution (200 μl) was added, and then reaction was carried out for about 24 hours while maintaining the temperature of the reaction vessel of 40° C. After TLC revealed the completion of reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in water (30 ml) and washed with ethyl acetate. Water was removed by distillation under reduced pressure to give a compound in the form of an oil. The compound thus obtained was purified by silica gel column chromatography (eluent: chloroform/methanol=4/1, v/v) to give the title compound (4.1 g, Yield 80%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:14]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[O:16])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>C(O)C.[Pd]>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:14]([C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[C:15]([NH:17][S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:26]=3)(=[O:20])=[O:19])=[O:16])=[CH:9][N:10]2[CH3:13])=[CH:6][CH:5]=1)(=[O:3])[NH2:2]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C(N)=O)ccc23)cc1

Procedure:
Ethyl (E)-3-(4-[2-(6-carbamoyl-1-methyl-1H-3-indolyl)-2-(1,3-benzodioxol-5-yl)acetyl]sulfamoylphenyl)-2-propenoate (the compound of Example 41, 0.24 g, 0.40 mmol) was dissolved in ethanol (5 ml) and 5% palladium-on-carbon (24 mg) was added. The mixture was placed in a pressure vessel and a hydrogen pressure of 345 kPa (50 psi) was maintained for 48 h. The reaction mixture was filtered through Arbocel™ and concentrated in vacuo. Flash column chromatography (elution with 5% methanol/90% dichloromethane) gave the product (70 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[C:15]3[N:16]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[CH:27]=3)[CH2:17][C:18](=[O:20])[NH:19][C:13]=2[CH:12]=[CH:11][CH:10]=1.O>CN(C)C=O>[Cl:1][C:27]1[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:16]2[C:15]=1[C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[NH:19][C:18](=[O:20])[CH2:17]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C1Cn2c(cc3ccccc32)-c2ccccc2N1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2c(c(Cl)c3ccccc32)-c2ccccc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A solution of 1.77 g N-chlorosuccinimide in 50 ml DMF (dimethylformamide) was added dropwise to a mixture of 3.0 g indolo[1,2-d][1,4]benzodiazepin-6(7H)-one in 50 ml dimethylformamide at room temperature. The resulting solution was stirred overnight at room temperature and then poured into 800 ml water. The precipitate was collected, washed with water and dried (P2O5) under vacuum to give 3.1 g solid, m.p. 287°-289° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[CH2:10][OH:11].[S:18]([O-])(=[O:21])(=[O:20])[CH3:19]>N1C=CC=CC=1>[CH3:19][S:18]([O:11][CH2:10][C:9]([O:15][CH2:16][CH3:17])([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][CH2:13][CH3:14])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)[O-]
Reactant: CCCC(CO)(OCC)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Product: CCCC(COS(C)(=O)=O)(OCC)c1ccc(Cl)cc1Cl

Procedure:
6.93 g (25 mmoles) of 2-(2,4-dichlorophenyl)-2-ethoxy-pentan-1-ol are dissolved in 20 ml of pyridine and converted into the corresponding mesylate by adding 3.15 g (27.5 mmoles) of methanesulfochloride. The reaction takes place exothermically with the precipitation of pyridine hydrochloride. After a reaction time of 1 hour, water is added and the mixture is extracted with diethyl ether. The combined extracts are washed with half-saturated sodium chloride solution, dried over sodium sulfate, filtered and freed from solvent in vacuo. Yield 8.6 g. 100 MHz-1H-NMR (CDCl3): δ=4.7 ppm ##STR37## 3.2-3.6 ppm (q, 2H, --OCH2CH3); 2.8 ppm (s, 3H, --OSO2CH3); 1.8-2.5 ppm (m, 2H, --CH2CH2CH3); 1.3 ppm (t, 3H, --OCH2CH3); 0.7-1.3 ppm (m, 5H, --CH2CH2CH3).
Reaction SMILES: I[CH2:2][CH2:3][OH:4].[N:5]1([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[C:22]4[N:23]=[CH:24][CH:25]=[N:26][C:27]=4[C:28]([C:31]4[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=4[Cl:42])=[CH:29][CH:30]=3)=[O:20])=[N:16][CH:17]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1>CC#N>[OH:4][CH2:3][CH2:2][N:8]1[CH2:7][CH2:6][N:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[C:22]4[N:23]=[CH:24][CH:25]=[N:26][C:27]=4[C:28]([C:31]4[C:36]([Cl:37])=[C:35]([O:38][CH3:39])[CH:34]=[C:33]([O:40][CH3:41])[C:32]=4[Cl:42])=[CH:29][CH:30]=3)=[O:20])=[N:16][CH:17]=2)[CH2:10][CH2:9]1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCNCC4)cn3)c3nccnc23)c1Cl
Reactant: OCCI
Solvent: CC#N
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(CCO)CC4)cn3)c3nccnc23)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 76.1 %

Procedure:
2-Iodoethanol (26 μL, 0.33 mmol, 10 equiv) was added to a mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (5-piperazin-1-ylmethyl-pyridin-2-yl)-amide (Example 105) (18 mg, 0.033 mmol) in CH3CN (1 mL), under an argon atmosphere. The reaction mixture was stirred for 14 h at rt, quenched by addition of a saturated aqueous solution of NaHCO3 (50 mL) and extracted with EtOAc. The organic layer was washed with a saturated aqueous solution of NaHCO3, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/NH3aq, 99:1→DCM/MeOH/NH3aq, 96:3:1) to afford 15 mg of the title compound as a yellow solid. Title compound: ESI-MS: 596.6/598.4 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.30 (DCM/MeOH, 9:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:10].[O:18]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)=[CH:21][N:20]=[CH:19]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:29]([C:26]2[CH:27]=[CH:28][C:23]([C:22]3[O:18][CH:19]=[N:20][CH:21]=3)=[CH:24][CH:25]=2)(=[O:30])=[O:31])=[C:3]([C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:4]=1
Reactant: Cc1ncccc1C(=O)c1cc(Cl)ccc1N
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure using (2-amino-5-chloro-phenyl)-(2-methyl-pyridin-3-yl)-methanone and 4-oxazol-5-yl-benzenesulfonyl chloride and purified by HPLC. MS: m/z 454 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][C:15]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH2:18]2)=[O:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:46]1([CH3:69])[CH:51]=[CH:50][C:49]([S:52]([O:55][CH2:56][CH2:57]OS(C2C=CC(C)=CC=2)(=O)=O)(=[O:54])=[O:53])=[CH:48][CH:47]=1>CN(C)C=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:8]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:39])[CH2:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:28][CH2:27]2)[CH2:18]1)=[O:16])[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:57][CH2:56][O:55][S:52]([C:49]2[CH:50]=[CH:51][C:46]([CH3:69])=[CH:47][CH:48]=2)(=[O:54])=[O:53])=[CH:3][CH:4]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1ccc(OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.9 %

Procedure:
100 mg (0.18 mmol) Tert-butyl 4-[3-((3R)-3-{[1-(4-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl)-3-oxopropyl]piperidine-1-carboxylate (example 2b) were dissolved in 7 ml N,N-dimethylformamide. 179 mg (0.55 mmol) cesium carbonate and 102 mg (0.28 mmol) ethylene glycol bis-p-toluenesulfonate were added. The mixture was stirred at room temperature for 48 hours and concentrated. The remainder was taken up with saturated ammonium chloride solution and ethyl acetate. The aqueous phase was extracted with 3×20 ml ethyl acetate. The extracts were dried over sodium sulfate and concentrated to yield 195 mg. Chromatography over 5 g silica gel (dichloromethane/ethanol 100/0-95/5) gave 95 mg (63%) tert-butyl 4-{3-[(3R)-3-({3-methoxy-1-[4-(2-{[(4-methylphenyl)sulfonyl]oxy}ethoxy)phenyl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][CH3:25])[C:9]1[CH:14]=[CH:13][C:12](B2[O:19][C:18]([CH3:21])(C)C(C)(C)O2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.O.[C:51](=[O:54])([O-])[O-:52].[Na+].[Na+]>COCCOC.O>[C:18]([OH:52])(=[O:19])[CH3:21].[C:51]([OH:52])(=[O:54])[CH3:1].[CH2:1]([N:8]([CH2:24][CH3:25])[C:9]1[CH:10]=[CH:11][C:12]([C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[N:29]([C@H:37]3[CH2:38][CH2:39][C@@H:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:41][CH2:42]3)[N:28]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(Cc1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CCN(Cc1ccccc1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A mixture of N-benzyl-N-ethyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.065 g, 0.000193 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.071 g, 0.000161 mol), tetrakis-(triphenylphosphine)palladium (0.011 g, 0.00001 mol) and sodium carbonate monohydrate (0.056 g, 0.00045 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-3-{4-[benzyl(ethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate (0.049 g, 0.000076 mol) as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:31][CH:30]=1)[C@H:3]([OH:27])[CH2:4][N:5]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22][C:23]#[N:24])[S:6]([C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1)(=[O:8])=[O:7].[O:43]1[CH2:47][CH2:46][C@H:45]([O:48][C:49](ON2C(=O)CCC2=O)=[O:50])[CH2:44]1.C(NC(C)C)(C)C.C(#N)C>>[O:13]1[C:12]2[CH:16]=[CH:17][C:9]([S:6]([N:5]([CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][CH2:22][C:23]#[N:24])[CH2:4][C@@H:3]([OH:27])[C@@H:2]([NH:1][C:49](=[O:50])[O:48][C@H:45]3[CH2:46][CH2:47][O:43][CH2:44]3)[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:34]=3)(=[O:8])=[O:7])=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: CC(C)(CCCC#N)CN(C[C@@H](O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: CC(C)(CCCC#N)CN(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)O[C@H]1CCOC1)S(=O)(=O)c1ccc2c(c1)OCO2

Procedure:
N-{(2R,3S)-3-Amino-4-[4-(benzyloxy)phenyl]-2-hydroxybutyl}-N-(5-cyano-2,2-dimethylpentyl)-1,3-benzodioxole-5-sulfonamide was treated with 1-({[(3S)-tetrahydro-3-furanyloxy]carbonyl}oxy)-2,5-pyrrolidinedione/diisopropylamine/acetonitrile as previously described to provide the title product as a solid foam. 1H NMR (DMSO-d6): δ 0.88 (3H, s), 0.90 (3H, s), 1.3 (2H, dd), 1.5-1.6 (2H, m), 1.7-1.8 (1H, m), 2.0-2.2 (1H, m), 2.37 (1H, t), 2.4 (2H, t), 2.75-2.85 (3H, m), 2.9 (1H, dd), 3.30-3.45 (3H, m), 3.55 (1H, dd), 3.65 (1H, dd), 3.7 (2H, dd), 4.9 (1H, s), 4.98 (1H, d), 5.0 (2H, s), 6.15 (2H, s), 6.8 (2H, d), 7.0 (2H, d), 7.06 (2H, d), 7.24 (1H, s), 7.25-7.42 (6H, m); MS: 708 (MH+);
Reaction SMILES: [NH2:1][C:2]1[C:29]([Cl:30])=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:31][CH2:32][CH3:33])[CH:3]=1.Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].[CH:47]1([CH2:50][NH2:51])[CH2:49][CH2:48]1>ClCCl.O>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([Cl:30])[C:2]([NH:1][C:35]([NH:51][CH2:50][CH:47]4[CH2:49][CH2:48]4)=[O:36])=[CH:3][C:4]=3[O:31][CH2:32][CH3:33])[CH2:13][CH2:12]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: NCC1CC1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: ClCCl
Product: CCOc1cc(NC(=O)NCC2CC2)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Reaction time: 0.5 h
Yield: 3 %

Procedure:
3-((4-(4-Amino-5-chloro-2-ethoxybenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (250 mg, 0.525 mmol) and 4-nitrophenol chloroformate (425.7 mg, 0.525 mmol) were combined and stirred in dichloromethane for 1 hour. Cyclopropylmethylamine (0.114 g, 1.6 mmol, 0.139 mL) was added and the reaction was stirred for 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic frit. The organic phase was concentrated under reduced pressure and purified by basic reverse phase HPLC to give the title compound (9.1 mg).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C1N2CCN(CC2)C1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:35][C:36]([NH:38][C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)=[S:37])=[O:34])=[CH:28][CH:27]=1>C(#N)C>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:32][C:33]([NH:35][C:36](=[S:37])[NH:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][C:2]3[C:7]4=[C:8]([CH3:16])[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][N:6]4[N:5]=[CH:4][N:3]=3)=[CH:41][CH:40]=2)=[O:34])=[CH:30][CH:31]=1
Reactant: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)cc1
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: CCOC(=O)c1cn2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3)c2c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a room temperature solution of ethyl 4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (7.2 mg, 0.03 mmol) (for preparation see U.S. Pat. No. 6,670,357, the disclosure of which is herein incorporated by reference) and DABCO (7 mg, 0.06 mmol) in acetonitrile (0.5 mL) was added 1-(2-(4-fluorophenyl)acetyl)-3-(4-hydroxyphenyl)thiourea (0.5 mL, 0.05 mmol). The reaction was shaken at room temperature. After 30 min, LC/MS analysis indicated mostly product. The reaction was stirred at room temperature overnight. The mixture was evaporated to dryness. Purification by silica gel chromatography (eluting with 1% methanol/dichloromethane) provided the desired product contaminated with impurities. A second purification by silica gel chromatography (1-6% Ethyl acetate/dichloromethane) again did not remove all of the impurities. The resulting solid mixture was washed with methanol and dried to provide the title compound (6 mg, 39%) as a yellow solid. 1H NMR (CDCl3) δ 12.32 (s, 1H), 8.62 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.76 (m, 2H), 7.29 (m, 4H), 7.12 (m, 2H), 4.38 (q, 2H, J=7.1 Hz), 3.72 (s, 2H), 2.82 (s, 3H), 1.40 (t, 3H, J=7.1 Hz); MS(ESI+) m/z 508 (M+H)+.
Reaction SMILES: [C:1]1([CH:7](Cl)[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].[SH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:20].C(O)C>O>[C:1]1([CH:7]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=2[O-:20])[CH2:8][CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [O-][n+]1ccccc1S
Reactant: CCCC(Cl)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCC(Sc1cccc[n+]1[O-])c1ccccc1
Reaction time: 2.5 h

Procedure:
A mixture of 16.9 gms (0.1 mol) of 1-phenylbutylchloride, 36 gms of a 40% aqueous solution of the sodium salt of 2-mercaptopyridine N-oxide (0.1 mol) and 50 ml of ethanol was warmed and stirred at 50° to 60° C. for 2.5 hours. The cooled reaction mixture was poured into 500 ml of water with agitation. The precipitated product was filtered, washed with water and dried. After recrystallization for ethanol a yield of 10 gms (45% theory) of white crystals was obtained.