Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[C:45]([C:47]1[CH:48]=[C:49]([CH:53]=[CH:54][CH:55]=1)[C:50](O)=[O:51])#[N:46]>CN(C=O)C.O>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:50](=[O:51])[C:49]2[CH:53]=[CH:54][CH:55]=[C:47]([C:45]#[N:46])[CH:48]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C#N)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
DIEA (527 mg, 4.07 mmol), HOBt (322 mg, 2.45 mmol), EDCI.HCl (302 m, 1.5 mmol) and piperazine-1-carboxylic acid tert-butyl ester (456 mg, 2.45 mmol) were added to a stirred solution of 3-cyano-benzoicacid (300 mg, 2.03 mmol) in DMF (3 mL) and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was then diluted with water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford 590 mg (92%) of 4-(3-cyano-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)=[O:10])[CH2:4][CH3:5].Cl.[C:19]1([CH2:25][S:26]([Cl:29])(=[O:28])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[ClH:29].[CH2:4]([N:3]([CH2:2][CH3:1])[CH2:6][CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][S:26]([CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:28])=[O:27])=[CH:13][CH:12]=1)=[O:10])[CH3:5]
Reactant: CCN(CC)CCNC(=O)c1ccc(N)cc1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CCNC(=O)c1ccc(NS(=O)(=O)Cc2ccccc2)cc1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of 7.1 g (0.026 moles) of procainamide hydrochloride in 100 ml acetone and 5 ml triethylamino at -50° C., is added slowly 5.0 g (0.026 moles) of α-toluenesulfonyl chloride. Stir at -50° C. for 1 hour, then warm to room temperature and stir for 16 hours. Remove the solvent in vacuo. Slurry the residue in 200 ml ether, and wash 2×100 ml portions of methylene chloride. The combined methylene chloride extracted are vacuum stripped to dryness. The residue is dissolved in 100 ml ethanol and brought to pH 3 with concentrated hydrochloric acid. The solvent is removed in vacuo, and the residue triturated with methylene-chloride to provide the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl.[Zn]>[C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]c3ccccc23)cc1
Agent: Cl
Agent: [Zn]
Product: c1ccc(C2CNc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
1.3 g of 3-phenylindole was suspended in 100 ml of 20% aqueous hydrochloric acid. The mixture was heated to 60° C. while stirring vigorously and 20 g of zinc dust was added thereto in small portions over a period of 45 minutes. On completing the addition of zinc dust, the reaction mixture was heated to 100° C. and maintained at this temperature for one hour, filtered hot, and the filtrate cooled to room temperature and washed with ether. The aqueous layer was basified with 50% aqueous sodium hydroxide and the desired product was extracted with ether and then purified by column chromatography using silica gel. The 3-phenylindoline was obtained in a yield of 0.8 g as a yellow viscous oil.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[CH:6]=1.[N:17]1([CH2:23][CH2:24][O:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl.O>[CH3:16][O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH3:3])[CH:6]=2)[C:11]=1[C:30]([C:29]1[CH:28]=[CH:27][C:26]([O:25][CH2:24][CH2:23][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:34][CH:33]=1)=[O:31]
Reactant: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Reactant: COc1ccc2cc(OC)ccc2c1
Agent: N#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OC)ccc2c1
Temperature: 0 °C
Yield: 68 %

Procedure:
In a dry round bottom flask equipped with stir bar, temperature probe and N2 line, dissolve 2,6-dimethoxynaphthalene (1.0 eq) in CH2Cl2 (5 volume equivalents) at ambient temperature. Cool the solution to 0° C. in with an ice bath, and add 4-(2-piperidin-1-yl-ethoxy)-benzoyl chloride (1.1 eq). Add aluminum chloride (2.0 eq). Once the reaction is determined to be complete, quench the reaction slowly with 1 N NaOH and dilute with additional water and CH2Cl2. Wash the aqueous layer with (1×20 mL) of CH2Cl2. Combine the organic extracts and wash with brine and dry (Na2SO4). Recrystallize the crude product from methanol to give (2,6-dimethoxy-naphthalen-1-yl)-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (average yield 68%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13].O([CH2:22][C:23]([F:26])([F:25])[F:24])S(C(F)(F)F)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:7]([CH2:9][CH3:10])=[N:8][C:4]=2[C:3]=1[Cl:13]
Reactant: CCc1nc2c(Cl)c(Br)ccc2[nH]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(Cl)c(Br)ccc2n1CC(F)(F)F
Temperature: 90 °C

Procedure:
5-Bromo-4-chloro-2-ethyl-1H-benzimidazole (0.049 g, 0.188 mmol), trifluoroethyl triflate (0.065 g, 0.282 mmol), and Cs2CO3 (0.092 g, 0.282 mmol) were combined in DMF (5 mL) and the resulting solution was heated to 90° C. for 30 min. The reaction mixture was partitioned between H2O and Et2O and further extracted with Et2O. The combined organic portions were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatography (SiO2, EtOAc/hexanes) allowed separation of the regioisomers. 0.083 g of desired regioisomer was isolated: 1NMR (400 MHz, CDCl3) δ 7.5 (d, J=8.5 Hz, 1H), 7.2 (d, J=8.5 Hz, 1H), 4.6 (q, J=8.3 Hz, 2H), 2.9 (q, J=7.4 Hz, 2H), 1.45 (t, J=7.4 Hz, 3H); MS (ESI) m/z 343 (M+1).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:29]([O:32][CH2:33][C:34](Cl)=[O:35])(=[O:31])[CH3:30]>C(Cl)Cl>[C:29]([O:32][CH2:33][C:34]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[CH2:15][C@H:14]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[O:13][C:12]3=[O:21])[CH:6]=2)[CH2:1]1)=[O:35])(=[O:31])[CH3:30]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reactant: CC(=O)OCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COC(C)=O)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A solution of N-[[(5S)-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (Example 1, Step 6, 350 mg, 1.21 mmol) and triethylamine (0.252 mL, 1.81 mmol) in dry CH2Cl2 (6 mL) under N2 is cooled to 0° C. and treated with acetoxyacetyl chloride (0.156 mL, 1.45 mmol). The resulting mixture is stirred at 0° C. for 1 hr and is then warmed to ambient temperature, diluted with CH2Cl2 (20 mL), washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude product is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-3/97), and those fractions with an Rf=0.44 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 323 mg (69%) of the title compound as a glassy solid. An analytical sample is prepared by trituration and filtration from Et2O. MS (ESI+) for C19H23N3O6 m/z 390 (M+H)+; Anal. Calcd for C19H23N3O6: C, 58.60; H, 5.95; N, 10.79. Found: C, 58.46; H, 6.06; N, 10.66; [α]25D =−18° (c 0.93, DMSO).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:14]=[C:13]([CH3:15])[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([O:3][C:4]2[CH:14]=[C:13]([CH3:15])[C:7]3[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=3[CH:5]=2)[CH:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1cc(O)cc2oc(=O)n(C)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
30 mg (0.70 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.12 g (0.70 mmol) 6-hydroxy-3,4-dimethyl-3H-benzoxazol-2-one in 5.0 ml DMF and the mixture was stirred for 10 min at RT. Then 0.10 g (0.70 mmol) 4,6-dichloropyrimidine was added and the mixture was stirred for 1 h at RT. Then water and EtOAc were added, the organic phase was separated off, dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:39]=[CH:40][CH:41]=2)[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19](=[CH:25][NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[CH:29][CH:28]=4)[C:20](=[O:24])[NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1.[CH2:43]1[CH2:47]N([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)C[CH2:44]1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.CON>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:39]=[CH:40][CH:41]=2)[C:13]([C:15]2[CH:23]=[C:22]3[C:18](/[C:19](=[CH:25]/[NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([O:38][CH:43]([CH3:47])[CH3:44])=[O:37])=[CH:29][CH:28]=4)/[C:20](=[O:24])[NH:21]3)=[CH:17][CH:16]=2)=[O:14])=[O:8])=[CH:5][C:4]([CH3:42])=[N:3]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCCC(=O)O)cc3)c2)n(C)n1
Agent: CON
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)/C4=C\Nc3ccc(CCCC(=O)OC(C)C)cc3)c2)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a dry 50 mL round bottomed flask, 4-{4-[(6-{3-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-benzoyl}-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-amino]-phenyl}-butyric acid (as prepared in Example 324, 50 mg, 0.088 mmol) was dissolved into DMF (1 mL), under Ar(g). PyBOP (60 mg, 0.115 mmol) was then added followed by triethyl amine (0.04 mL, 0.266 mmol) and O-methylhydroxylamine hydrochloride (22 mg, 0.264 mmol). The mixture was stirred at room temperature for 2 h after which the reaction mixture was partitioned between EtOAc (˜10 mL) and brine (10 mL). The organic layer was extracted with brine (3×˜10 mL). The organic layers were combined and then concentrated in vacuo. The crude mixture was then chromatographed over silica (EtOAc/MeOH gradiant was used starting from 1% MeOH up to 5% MeOH). The title compound was isolated in pure form as a yellow solid (27.8 mg, 0.046 mmol, 53%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[CH2:17][CH2:16]3)[C:8]=2[CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[ClH:29].[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][CH2:21][N:18]2[CH2:19][CH2:20][N:15]([C:14]3[C:8]4[CH:7]=[C:6]([CH2:4][OH:3])[S:10][C:9]=4[CH:11]=[CH:12][CH:13]=3)[CH2:16][CH2:17]2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1cc2c(N3CCN(CCc4ccc(Cl)cc4)CC3)cccc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cl
Product: OCc1cc2c(N3CCN(CCc4ccc(Cl)cc4)CC3)cccc2s1
Yield: 150.1 %

Procedure:
In an analogous manner to example 2, the title compound (0.89 g) as a white solid, mp 248°-249° C. dec., is prepared from ethyl-4-[4-[2-(4-chlorophenyl)ethyl]-1-piperazinyl]-benzo[b]thiophene-2-carboxylate (1.20 g, 2.80 mmol, prepared in example 18) and lithium aluminum hydride (0.21 g, 5.6 mmol). The title compound is recrystallized from methanol (25 mL) and acetonitrile (10 mL); 1H NMR (CD3OD) δ 7.58 (1H, d, J=8.8 Hz), 7.37 (5H, m), 7.28 (1H, t, J=7.9 Hz), 7.00 (1H, d, J=7.8 Hz), 4.87 (2H, s), 4.07 (9H, m), 3.15 (3H, m); 13C NMR (CD3OD) δ 147.91, 147.51, 143.38, 136.81, 135.92, 134.81, 132.01, 130.62, 126.45, 119.92, 119.85, 114.46, 61.25, 59.20, 54.33, 51.01, 31.17; IR (KBr) 3319, 2584, 1462, 1446, 958, 779 cm-1 ; CI/MS 387(100%). IC50 =2 nM (5HT1ABinding Affinity) IC50 =10 nM (5HT1DBinding Affinity)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([O-:14])=[O:13])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)[O-])(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 93 %

Procedure:
To a stirred solution of 7.58 g (22.0 mmol) of diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI in 50 ml of absolute ethanol, maintained under nitrogen gas at ~15° C. (ice bath) is added 8.72 g (109.0 mmol, 5.0 mol-equiv.) of 50% aqueous sodium hydroxide. The temperature is maintained at <25° C. for 6 hours. The resulting suspension is diluted with 150 ml water and the pH is adjusted to ~8.0 with dilute hydrochloric acid. The solution is transferred to a separatory funnel and is extracted with 3×60 ml of methylene chloride. The aqueous layer is acidified to pH <1 with concentrated hydrochloric acid and is then extracted with 200 ml of ethyl acetate in three portions. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.9 g 2-(2-fluoro-4-biphenylyl)-2-methyl malonic acid. This material is dissolved in 15 ml of glacial acetic acid and the solution is heated to reflux for ~17 hours. Water (15 ml) is added and the solution is allowed to cool slowly with stirring and seeding. After 1 hour stirring at room temperature, the mixture is cooled with stirring to 0°-5° C., then let stand for ~15 hours. The product is isolated and washed with a few ml of cold 50% aqueous acetic acid then dried to give 4.67 g flurbiprofen Ib of melting point 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:18])[N:15]=[C:14](Cl)[CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:20][NH2:21].[ClH:22].CO>CO.C(OCC)C>[ClH:18].[ClH:22].[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:21][CH3:20])[N:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(Cl)c2)cc1
Reactant: CN
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)cc(Cl)n1
Yield: 41 %

Procedure:
0.11 g (0.00035 mol) of 4-amino-N-(2,6-dichloro-pyridin-4-yl)-benzenesulfonamide was stirred in 25 ml of liquid methylamine in an autoclave at 130° C. for 72 hours. After removal of the methylamine the residue was taken up in 5 ml of dichloromethane/methanol 1:1, filtered and, after removal of the solvent, chromatographed on silica gel with hexane/ethyl acetate 3:1, 2:1 and finally 1:1. The product, obtained as a white, amorphous solid substance, was dissolved in 2 ml of methanol, treated with 2 ml of 2N HCl/methanol, diluted with 20 ml of diethyl ether and filtered off under suction. The material on the suction filter was washed well with diethyl ether and dried in a high vacuum. There was obtained 0.055 g (41%) of 4-amino-N-(2-chloro-6-methylamino-pyridin-4-yl)-benzenesulfonamide dihydrochloride (1:2) as white crystals; m.p.: >215° C. (dec.).
Reaction SMILES: C([Sn](CCCC)(CCCC)/[CH:6]=[CH:7]/[CH2:8][CH:9]([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])CCC.[I:30]I>CCOCC>[I:30]/[CH:6]=[CH:7]/[CH2:8][CH:9]([O:14][Si:15]([CH2:20][CH3:21])([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: II
Reactant: CCCCC(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Solvent: CCOCC
Product: CCCCC(C/C=C/I)O[Si](CC)(CC)CC

Procedure:
To a solution of E-1-tri-n-butystannyl-4-triethylsilyloxy-1-octene (11 g) in 200 ml ether is added 0.9 equivalents of iodine in one portion. After 25 minutes the color of the iodine has disappeared. An additional 0.1 equivalents of iodine is added in portions until the iodine color persists. The ether is removed in vacuo to provide (E)-1-iodo-4-triethylsilyloxy-1-octene. This residue is placed on a silica-gel column (240 g SilicAR CC-7) packed in hexane. A liter fraction of hexane contains 7.5 g of mostly tri-n-butyliodostannane. A 500 ml elution of benzene gives only a small amount of material. An elution with 600 ml of ether provides 7.0 g of 1-iodo-4-hydroxy-1-octene as an oil.
Reaction SMILES: [CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][N:40]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[N:41]1>ClCCl>[CH3:1][CH:2]([N:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([S:45]([C:42]2[CH:43]=[CH:44][N:40]([CH3:39])[N:41]=2)(=[O:47])=[O:46])[CH2:6][CH2:5]1
Reactant: CC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CN1CCN(S(=O)(=O)c2ccn(C)n2)CC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a mixture of 4-[1-(1-methyl-2-piperazin-1-ylethyl)-1H-pyrazol-4-yl]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (1.1 g, 2.5 mmol) in dichloromethane (20 mL) was added triethylamine (0.52 mL, 3.7 mmol) followed by 1-methyl-1H-pyrazole-3-sulfonyl chloride (0.54 g, 3.0 mmol). The reaction was stirred at RT for 1 h, then quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. After being concentrated to dryness, the residue was purified on silica gel, eluting with 0 to 10% methanol in dichloromethane to provide the product (1.28 g, 87.7%). LCMS calculated for C26H40N9O3SSi (M+H)+: m/z=586.3; Found: 586.2. The product was separated on a ChiralCel OD-H column (3×25 cm, 5 μM), eluting with a gradient of ethanol in hexanes at flow rate 28 mL/min, to give the two enantiomers. First peak with retention time 20.76 min and second peak with retention time 24.72 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN.O.O[N:22]1[C:26]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[CH3:26][NH:22][C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of N-[(benzyloxy)carbonyl]-β-alanine (10 g, 44.8 mmol), methylamine hydrochloride (3.33 g, 49.28 mmol), 1-hydroxybenzotriazole hydrate (6.05 g, 44.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g, 53.76 mmol) and N-methylmorpholine (11.33 ml, 103 mmol) in dichioromethane (200 ml) was stirred at room temperature for 18 hours. The resulting precipitate was filtered off to give the desired product as a colourless foam, and the filtrate evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:hexane (90:10 to 100:0) to give additional product, 7.96 g, 75% in total; 1H NMR (CDCl3, 300 MHz) δ: 2.42 (t, 2H), 2.80 (s, 3H), 3.50 (m, 2H), 5.21 (s, 2H), 5.49 (bs, 1H), 5.63 (bs, 1H), 7.36 (m, 5H); Anal. Found: C, 60.68; H, 7.00; N, 11 .95. C12H16N2O3 requires C, 61.00; H, 6.83; N, 11.86%.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>CN(C)C=O>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:22]=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[C:12](=[O:23])[C:11]1=[CH:26][N:27]([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)[C@H](n2ccc(=O)[nH]c2=O)O1
Solvent: CN(C)C=O
Product: CN(C)C=C1C(=O)[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
5'-O-(t-Butyldimethylsilyl)-2',3'-dideoxy-2'-oxo-uridine (2.2 g, 6.45 mmol) was dissolved in 25 mL of dry dimethylformamide (DMF) and 0.85 g (7.1 mmol) of N,N-dimethylformamide dimethyl acetal was added. The reaction mixture was heated to 50° C. under a nitrogen atmosphere and stirred for 0.5 h. The solvent was removed in vacuo and the residue (3.2 g) was dissolved in methylene chloride and purified by flash chromatography (5 psi) on a silica gel column (2×25 cm) eluted with 200 mL of methylene chloride, 200 mL of 2% methanol in methylene chloride and 200 mL of 5% methanol in methylene chloride to give 1.78 g (70% yield) of the title compound MS DCI: 396 (M+H)+, 418 (M+Na)+
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C@@H:15]([CH2:16][F:17])[CH2:14][N:13]([C:18]([O:20]C(C)(C)C)=O)[CH2:12]3)=[C:8]([C:25](=[O:27])[NH2:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH2:29]([N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1)C.[C:45]([C:47]1(C(O)=O)[CH2:49][CH2:48]1)#[N:46]>>[C:45]([C:47]1([C:18]([N:13]2[CH2:14][C@H:15]([CH2:16][F:17])[C@H:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:34]5[CH:33]=[N:32][N:31]([CH3:29])[CH:35]=5)[N:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:26])=[O:27])[CH2:12]2)=[O:20])[CH2:49][CH2:48]1)#[N:46]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: N#CC1(C(=O)O)CC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CF)[C@H](Nc2c(C(N)=O)cnn3cc(Br)nc23)C1
Product: Cn1cc(-c2cn3ncc(C(N)=O)c(N[C@@H]4CN(C(=O)C5(C#N)CC5)C[C@@H]4CF)c3n2)cn1

Procedure:
According to the procedure described for Example 56, Example 57 was prepared from (3S,4S)-tert-butyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (from Step 2 of Example 56) via Suzuki coupling reaction with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole under conditions similar to Step 3 of Example 56, deprotection of N-Boc under conditions similar to Step 3 of Example 56 and amidation with 1-cyanocyclopropanecarboxylic acid under conditions similar to Step 5 of Example 56.