Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([O:8][Si:9]([CH3:12])([CH3:11])[CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[Li]CCCC.CON(C)[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C1COCC1>[N:25]1[CH:26]=[CH:27][C:22]([C:21](=[O:28])[C:2]#[C:1][C:3]2([O:8][Si:9]([CH3:10])([CH3:12])[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:23][CH:24]=1
Reactant: C#CC1(O[Si](C)(C)C)CCCC1
Reactant: CON(C)C(=O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1(C#CC(=O)c2ccncc2)CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.6 %

Procedure:
To a stirred solution of (1-ethynylcyclopentyloxy)trimethylsilane (2.0 g, 11.0 mmol) in dry THF (50 mL) was added n-BuLi (20.0 mL, 20.0 mmol, 1.6 M in hexane) drop wise at −78° C. under an inert atmosphere for a period of 10 min. After being stirred for 30 min at −78° C., a solution of compound N-methoxy-N-methylisonicotinamide (2.1 g, 13.2 mmol) in dry THF (10 mL) was added to the reaction mixture and stirring was continued for an additional 2 h at −78° C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2×60 mL). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 5% EtOAc in Hexane to afford 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl) prop-2-yn-1-one (1.0 g, 32%) as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([O:19][CH3:20])[CH:13]=1)(=[O:10])[O:6][CH2:7][CH2:8][OH:9].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([NH:33][CH3:34])=[O:32])[C:25]([C:39]([F:42])([F:41])[F:40])=[CH:24][N:23]=1>>[OH:9][CH2:8][CH2:7][O:6][P:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:22]2[N:27]=[C:26]([NH:28][C:29]3[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=3[C:31](=[O:32])[NH:33][CH3:34])[C:25]([C:39]([F:42])([F:40])[F:41])=[CH:24][N:23]=2)=[C:14]([O:19][CH3:20])[CH:13]=1)(=[O:10])[O:4][CH2:3][CH2:2][OH:1]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1cc(CP(=O)(OCCO)OCCO)ccc1N
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCCO)OCCO)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 using bis(2-hydroxyethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 113A, 30 mg, 0.1 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide (Compound 104A, 33 mg, 0.1 mmol). The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.83 (s, 3H), 3.35 (d, J=21.6 Hz, 2H), 3.60 (dd, J=5.2, 10.4 Hz, 4H), 3.84 (s, 3H), 3.99-4.03 (m, 4H), 4.95 (t, J=5.2 Hz, 2H), 6.92 (d, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.45 (m, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.73 (dd, J=1.2, 8.0 Hz, 1H), 8.43 (s, 1H), 8.48 (m, 1H), 8.80 (m, 2H), 11.49 (s, 1H). MS (ES+): m/z 600.11 [MH+]; HPLC: tR=2.80 min (ZQ3, polar—5 min).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:3].[P:23]([O:28]C)([O:26][CH3:27])[O:24][CH3:25]>>[CH2:5]([O:4][C:2]([P:23](=[O:28])([O:26][CH3:27])[O:24][CH3:25])=[O:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COP(OC)OC
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)Cl
Product: CCCCCCCCCCCCCCCCCCOC(=O)P(=O)(OC)OC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of octadecyl chloroformate (7.0 g, 21 mmol) and P(OMe)3 (37.2 mL) was stirred at 80° C. for 2 hours and allowed to cool overnight. The white solid of the title compound which formed was collected, washed with hexane, and dried overnight in a vacuum oven; yield 6.0 g. A second crop was obtained from the filtrate upon cooling (2.1 g); total yield 8.1 g (95%); mp 41-42° C. (hexane); IR (KBr): υ 2950-2880, 2830, 1710, 1470, 1375, 1350, 1280, 1220 cm−1; 1H NMR (CDCl3) δ 0.8-1.8 (m, 35H, CH3 (CH2)16), 3.9 (d, 6H, P(OCH3)2), 4.3 (t, 2H, CH2O). Anal. Calcd. for C21H43O5P: C, 62.03; H, 10.68; P, 7.62. Found: C, 62.16; H, 10/71; P, 7.69.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9](O)=[O:10])=[N:2]1.C1C=CC=CC=1.S(Cl)([Cl:28])=O>C(N(CC)CC)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([Cl:28])=[O:10])=[N:2]1
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1-c1ccon1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Cl)ccc(S(C)(=O)=O)c1-c1ccon1

Procedure:
To 0.55 g of 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoic acid were added 10 ml of benzene, then 0.17 ml of thionyl chloride and a drop of triethylamine to heat at reflux for 2 hours. The reaction solution was cooled down. The solvent was distilled out under reduced pressure to give 3-(isoxazol-3-yl)-4-methylsulfonyl-2-methylbenzoyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:28])=[C:4]([CH:19]=[N:20][C:21]([O:23][Si](C)(C)C)=[CH2:22])[C:5]([O:8][CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C)C)=[CH:6][CH:7]=1.C(OC([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)/[C:38](=[CH:46]/[C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=2)/[C:37]1=[O:54])=O)(C)(C)C.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([F:28])=[C:4]([CH:19]2[C:38]3([C:39]4[C:44](=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=4)[NH:36][C:37]3=[O:54])[CH:46]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([Cl:53])[CH:48]=3)[CH2:23][C:21](=[O:22])[NH:20]2)[C:5]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: C=C(N=Cc1c(OCCO[Si](C)(C)C(C)(C)C)ccc(Br)c1F)O[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2c(OCCO)ccc(Br)c2F)N1
Temperature: 140 °C
Reaction time: 0.75 h
Yield: 65.6 %

Procedure:
To a solution of 1-{3-bromo-2-fluoro-6-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenyl}-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 183c in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in example 24a (0.5 g, 1.28 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 45 min. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was dissolved in tetrahydrofuran (10 mL) and tetrabutylammonium fluoride solution (1M in THF, 10 mL) was added. The reaction mixture was stirred at room temperature for 10 min, then poured into water and extracted with ethyl acetate. The combined organic layer was dried over MgSO4 and concentrated. The residue was purified by chromatography to give racemic (2′R,3R,4′S)-2′-[3-bromo-2-fluoro-6-(2-hydroxy-ethoxy)-phenyl]-6-chloro-4′-(3-chlorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a yellow solid (Yield 0.4 g, 65.6%).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][S:16]([C:19]2[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=2[CH3:27])(=[O:18])=[O:17])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CN(C=O)C>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[N:15]([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][Br:30])[S:16]([C:19]2[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])(=[O:17])=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCBr
Reactant: Cc1cc(C)c(S(=O)(=O)Nc2c3ccccc3nc3ccccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(S(=O)(=O)N(CCCCCBr)c2c3ccccc3nc3ccccc23)c(C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
A solution of 450 mg (1.20 mmol) of N-(9-acridyl)-mesitylenesulfonamide in 20 mL of DMF was placed under an atmosphere of argon and cooled to 0° C. To the cooled solution was added 36 mg (1.42 mmol) of NaH (95%). The reaction mixture was stirred at 0° C. for 5 min and at room temperature for 1 hr. Then the reaction mixture was cooled to 0° C., and 1.65 mL (12.1 mmol) of 1,5-dibromopentane were added. The reaction mixture was stirred at 70-80° C. for 23 hr. The reaction mixture was cooled, and quenched with 20 mL of water. The mixture was partitioned between CH2Cl2 and water. The aqueous phase was washed with CH2Cl2 (2×20 mL). The CH2Cl2 washes were combined with the organic phase, dried with MgSO4, and evaporated to dryness. The material was purified by column chromatography on silica gel with CH2Cl2 to afford 382.2 mg (60%) of bromide 42 as an orange oil: 1H NMR (300 MHz, CDCl3, TMS) δ 8.25 (d, J=9 Hz, 2H), 7.94 (d, J=9 Hz, 2H), 7.76 (t, J=8 Hz, 2H), 7.45 (t, J=8 Hz, 2H), 6.87 (s, 2H), 4.0-3.9 (m, 2H), 3.27 (t, J=6.5 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 6H), 1.8-1.6 (m, 4H), 1.4-1.3 (m, 2H).
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][N:14]2[C:18]([C:19](OCC)=[O:20])=[CH:17][C:16]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:15]2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1.C(Cl)Cl>[OH:10][CH2:11][C@@H:12]1[CH2:13][N:14]2[N:15]=[C:16]([CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=[C:18]2[C:19](=[O:20])[NH:8]1
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1N[C@H](CO)Cn2nc(COc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
(S)-4-(5-Ethoxycarbonyl-3-phenoxymethyl-pyrazol-1-ylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.91 g, 1.9 mmol) was dissolved in a 4M solution of HCl in dioxane (9.8 mL) and the solution was stirred at room temperature for 1 hour. The solvent was evaporated in vacuo and the residue was taken up in MeOH (10 mL) and K2CO3 (0.82 g, 5.96 mmol) was added. The mixture was stirred at 100° C. for 5 minutes under microwave irradiation. Then mixture was diluted with DCM. The solid was filtered off and the filtrate solvent was evaporated in vacuo. The residue was purified by flash column chromatography (silica, MeOH in AcOEt 0/100 to 10/90). Desired fractions were collected and the solvents evaporated in vacuo to yield (S)-6-hydroxymethyl-2-phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (0.33 g, 61% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.27-3.33 (m, 1H), 3.46-3.54 (m, 1H), 3.73-3.84 (m, 1H), 4.30 (dd, J=13.4, 5.8 Hz, 1H), 4.38 (dd, J=12.9, 5.3 Hz, 1H), 5.05 (s, 2H), 5.18 (br. s., 1H), 6.77 (s, 1H), 6.91-6.98 (m, 1H), 6.99-7.07 (m, 2H), 7.25-7.35 (m, 2H), 8.26 (d, J=2.5 Hz, 1H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][C@@H:17]1[C:33](=[O:34])[N:19]2[C:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[C:21]([CH2:24][CH3:25])[CH2:22][S:23][C@H:18]12.[C:35]1([CH2:41][C:42](O)=[S:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.N=C=N>C(Cl)Cl>[CH2:24]([C:21]1[CH2:22][S:23][C@@H:18]2[C@H:17]([NH:16][C:42](=[S:43])[CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33](=[O:34])[N:19]2[C:20]=1[C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH3:25]
Reactant: OC(=S)Cc1ccccc1
Reactant: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N=C=N
Solvent: ClCCl
Product: CCC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=S)Cc3ccccc3)[C@H]2SC1
Reaction time: 2 h

Procedure:
A solution of N,N'-dicyclohexylcarbodiimide (620 mg, 3 mmole) in dry methylene chloride (15 ml.) was added to a stirred solution of t-butyl 7β-amino-3-ethylceph-3-em-4-carboxylate (853 mg. 3 mmole) in dry methylene chloride (10 ml.). A solution of phenylthioacetic acid (505 mg. 3 mmole) in dry methylene chloride (10 ml.) was added over 5 minutes to the mixture which was stirred at ca. 20° for 2 hours. A further portion of carbodiimide (124 mg., 0.6 mmole) was added, and the mixture was stirred for a further 30 minutes and filtered from precipitated N,N'-dicyclohexylurea. The filtrate was washed successively with 3% aqueous sodium hydrogen carbonate solution (50 ml.), water (50 ml.), 2N-hydrochloric acid (25 ml.) and water (25 ml.), dried (MgSO4) and evaporated to a yellow oil which was dissolved in ethyl acetate (8 ml.). The solution was cooled, the precipitated dicyclohexylurea was removed by filtration, and the filtrate was evaporated to give the title ester as a pale yellow foam (1.45 g.), [α]D23 + 67° (c 1.05; CHCl3), λmax. (EtOH) 250.5 nm (E1 cm.1% 256), contaminated with ca. 15% by weight of N,N'-dicyclohexylurea and/or the corresponding N-acylurea. The infra red (CHBr3) and p.m.r. (CDCl3) spectra of the product were in accord with the assigned structure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:23]=1.[Cl:31][C:32]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[C:34]([Cl:47])[C:33]=1[OH:48]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][CH2:29][CH2:30]4)[CH:23]=2)=[CH:3][C:2]([C:36]2[CH:37]=[C:32]([Cl:31])[C:33]([OH:48])=[C:34]([Cl:47])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1cncc(CCN2CCCC2)c1)C1CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1cncc(CCN2CCCC2)c1)C1CC1
Yield: 45.7 %

Procedure:
Following general procedure A-1, {6-bromo-4-[5-(2-(pyrrolidin-1-yl)ethyl)pyridin-3-ylamino]quinolin-3-yl}(cyclopropyl)methanone (54 mg, 0.116 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (50 mg, 0.174 mmol) to afford the desired product (29 mg, 46%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.36 (s, 1H), 8.64 (dd, J=16.9, 2.1 Hz, 2H), 8.32 (dd, J=8.8, 2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.99 (t, J=2.0 Hz, 1H), 7.43 (s, 2H), 3.74-3.70 (m, 2H), 3.50-3.43 (m, 2H), 3.24-3.17 (m, 2H), 3.16-3.12 (m, 2H), 2.79-2.76 (m, 1H), 2.19-2.15 (m, 2H), 2.07-2.03 (m, 2H), 1.18-1.07 (m, 4H); ESI MS m/z 547 [C30H28Cl2N4O2+H]+; HPLC>99% (AUC), tR=9.93 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:24])=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:36])(C)(C)C>O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[C:17]([CH3:24])=[CH:18][C:19]([C:22]([NH2:23])=[O:36])=[N:20][CH:21]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C#N)cc1C
Reactant: CC(C)(C)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(C(N)=O)cc1C
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
A mixture of 5-[10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazol-1-yl]-4-methylpyridine-2-carbonitrile (Example 59; 70.0 mg, 0.172 mmol), potassium hydroxide (38.5 mg, 0.687 mmol) and t-butyl alcohol (2 mL) was stirred at 80° C. for 15 min. After the reaction mixture was diluted with water at 0° C., the precipitate was collected by filtration and washed with water and diisopropyl ether to give the title compound as a solid (64.8 mg, 0.152 mmol, 88%). Analytically pure material was obtained by recrystallization from ethyl acetate/n-hexane.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].F[C:23](F)(F)[C:24]([OH:26])=O.[Cl:29][C:30]1[CH:31]=[N:32][C:33]2[NH:34][C:35]3[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=3)[CH2:40][CH2:41][C:42]3[CH:50]=[C:46]([NH:47][C:48]=1[N:49]=2)[CH:45]=[CH:44][C:43]=3[NH:51][CH2:52][CH2:53][CH:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1.C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18].[C:24]([N:57]1[CH2:58][CH2:59][CH:54]([CH2:53][CH2:52][NH:51][C:43]2[CH:44]=[CH:45][C:46]3[NH:47][C:48]4[N:49]=[C:33]([NH:34][C:35]5[CH:36]=[N:37][CH:38]=[C:39]([CH:60]=5)[CH2:40][CH2:41][C:42]=2[CH:50]=3)[N:32]=[CH:31][C:30]=4[Cl:29])[CH2:55][CH2:56]1)(=[O:26])[CH3:23]
Reactant: Clc1cnc2nc1Nc1ccc(NCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCC(CCNc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-N-(2-piperidin-4-ylethyl)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tetrakis(trifluoroacetate) and acetyl chloride as the starting materials in 50% yield. LCMS for C26H31ClN7O (M+H)+: m/z=492.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][C:2]1([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:22][S:19]([O:11][CH2:10][CH2:9][C:2]1([CH2:6][CH2:7][O:8][S:19]([CH3:22])(=[O:21])=[O:20])[O:3][CH2:4][CH2:5][O:1]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC1(CCO)OCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC1(CCOS(C)(=O)=O)OCCO1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,2′-(1,3-dioxolane-2,2-diyl)diethanol (1.3 g, 8.0 mmol) in methylene chloride (100 mL) was added triethylamine (3.4 mL, 24 mmol) at room temperature. The solution was cooled down to −40° C. and then mesyl chloride (1.65 mL, 20 mmol) was added dropwise. The reaction mixture was stirred at −40° C. for 30 min, then warmed up to 0° C. gradually. The reaction was quenched with saturated aqueous NaHCO3 solution. The aqueous layer was extracted with methylene chloride. The combined organic extracts were washed with brine, dried over Na2SO4, then evaporated to afford the crude product, 1,3-dioxolane-2,2-diyldiethane-2,1-diyl dimethanesulfonate: MS (m/e): 319 (M+1)+.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C1(C)C=CC=CC=1>[C:1]1([S:7][CH2:8][C:9]([Cl:15])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CSc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CSc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 5.0 g of (phenylthio)acetic acid in 20 ml of toluene under nitrogen was added 5.2 ml of oxalyl chloride in four portions. The solution was stirred at room temperature for about twenty hours and then concentrated in vacuo to the oily title compound, which was used in subsequent reactions without further purificaton or characterization.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].N#N>O.O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([CH:31]3[CH2:33][CH2:32]3)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)C1CC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Clc1cc2c(cn1)c(C1CC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.8 %

Procedure:
To a flask were added 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (3a, 2 g, 3.83 mmol), cyclopropylboronic acid (0.560 g, 6.52 mmol)), potassium carbonate (1.3 g, 9.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii) dichloride dichloromethane complex (0.157 g, 0.192 mmol), dioxane (10 ml), and water (5 ml). The mixture was Vac/N2 purged 6 times and heated at 60° C. After 5 h, the reaction was treated further with cyclopropylboronic acid (0.560 g, 6.52 mmol)), potassium carbonate (1.3 g, 9.6 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(ii)dichloride dichloromethane complex (0.157 g, 0.192 mmol), then degassed, and then heated at 80° C. overnight. The mixture was diluted with DCM and water and then filtered through celite. The organic phase was separated and concentrated to afford a dark residue, which was purified on silica gel (40 g, 0-20% ethyl acetate/hexanes) to afford 6-chloro-3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridine (1.4 g, 84% yield) as a white foam. MS ESI calc'd. for C28H22Cl1N3[M+1]+ 436, found 436.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)[N:3]=1.[H][H]>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:32]2[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CC1Cc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1Cc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-3,6-dihydropyridine-1(2H)-carboxylate (Example 43, Step 1) (0.20 g, 0.38 mmol) in methanol (5 mL) was added palladium on carbon 10% wt. (20 mg) under an atmosphere of nitrogen. The mixture was vacuumed and re-charged with hydrogen three times, and stirred at r.t. for 48 h. The mixture was filtered. The filtrate was concentrated to afford the desired product which was directly used in next step reaction without further purification (200 mg, 99.61%). LCMS (M+H)+: m/z=522.3.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ncccc2O)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncc(Sc2ncccc2O)s1
Yield: 68.2 %

Procedure:
A mixture of 2-acetylamino-5-(3-hydroxypyridin-2-ylthio)thiazole (2 g) in a mixture of ethanol (40 ml), tetrahydrofuran (20 ml) and aqueous 6N-hydrochloric acid (13 ml) was refluxed for 5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate and extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give 2-amino-5-(3-hydroxypyridin-2-ylthio)thiazole (1.15 g, yield: 68.9%).