Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:9][CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5]1)=[C:2]=[S:3].[C:17](Cl)(=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC1C=CC=CC=1>[N:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])[CH2:6][CH2:5]1)=[C:2]=[S:3]
Reactant: S=C=NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(N=C=S)CC1
Reaction time: 8 h
Yield: 97 %

Procedure:
To a stirred solution of 28.4 parts of 4-isothiocyanato-1-(phenylmethyl)piperidine in 315 parts of methylbenzene are added dropwise 41 parts of (phenylmethyl) carbonochloridate at room temperature. Upon completion, the whole is heated to reflux and stirring is continued overnight at reflux temperature. The reaction mixture is cooled and the solvent is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 32 parts (97%) of (phenylmethyl) 4-isothiocyanato-1-piperidinecarboxylate as a residue.
Reaction SMILES: O[CH:2]1O[C:5](=[O:7])[CH:4]=[C:3]1[CH3:8].Cl.[NH:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:11]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:10]1[C:5](=[O:7])[CH:4]=[C:3]([CH3:8])[CH:2]=[N:11]1)[CH3:17]
Reactant: CC1=CC(=O)OC1O
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc(C)cc1=O

Procedure:
5-Hydroxy-4-methylfuran-2(5H)-one (1.19 g, 10.4 mmol) and ethyl hydrazinoacetate hydrochloride (1.61 g, 10.4 mmol) in 95% ethanol (20 mL) was refluxed for 2 h. Removal of the solvent in vacuo followed by purification using a Biotage Horizon® system (0-50% ethyl acetate/hexanes mixture) gave ethyl[4-methyl-6-oxopyridazin-1(6H)-yl]acetate as a yellow crystalline. LC/MS 219.2 (M+23).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[O:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[O:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:36]3[CH:37]=[N:38][C:39]([NH2:42])=[N:40][CH:41]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3o2)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3o2)CC1

Procedure:
2-Chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidine, prepared in Example 153) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure E to give, after purification by reverse HPLC, 4 mg of 5-(6-((4-methylsulfonylpiperazin-1-yl)methyl)-4-morpholinofuro[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine. MS (Q1) 475 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH:30]1([NH2:33])[CH2:32][CH2:31]1>>[CH:30]1([NH:33][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:32][CH2:31]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: NC1CC1
Product: Cc1ccccc1-c1cc2c(NC3CC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropyl amine in step E. MS (ESI): predicted mass calcd. for C22H18ClN5O2, 419.9
Reaction SMILES: C(O[C:4](=[O:16])[CH2:5][NH:6][C:7](=[O:15])[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])C.[NH3:17]>CO>[O:14]=[C:10]1[CH2:11][CH2:12][CH2:13][N:9]1[CH2:8][C:7]([NH:6][CH2:5][C:4]([NH2:17])=[O:16])=[O:15]
Reactant: CCOC(=O)CNC(=O)CN1CCCC1=O
Reactant: N
Solvent: CO
Product: NC(=O)CNC(=O)CN1CCCC1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
17.1 g (0.075 mole) of N-(2-oxo-1-pyrrolidineacetyl)-glycine ethyl ester are dissolved in 350 ml of methanol. The solution is saturated with a current of ammonia (about 2 hours), stirring is maintained for 3 hours at ambient temperature. After the reaction mixture has been evaporated to dryness in vacuo, the residue crystallizes quickly, 14.9 g of 2-(2-oxo-1pyrrolidineacetamido)-acetamide being obtained (yield: 100% of theory); M.P. 147°-148° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:14])=[C:8]([S:10]([NH2:13])(=[O:12])=[O:11])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CCO>[NH2:14][C:7]1[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][C:8]=1[S:10]([NH2:13])(=[O:11])=[O:12]
Reactant: CC(=O)c1ccc(N)c(S(N)(=O)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc(N)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.8 %

Procedure:
5-Acetyl-2-aminobenzenesulfonamide (see compound 13) (0.95 g, 4.4 mmol) was suspended in 96% EtOH (50 ml) and NaBH4 (0.46 g, 12 mmol) was added in one portion. The mixture was stirred at 25° C. for 4 h and filtered through Celite and the solvent was removed under reduced pressure. The residue was treated with sat. NaHCO3 (50 ml) and extracted with EtOAc (2×50 ml), dried (Na2SO4) and evaporated to dryness. Flash-chromatography with EtOAc:n-hexane:Et3N (200:100:4, v/v/v) as eluent gave 0.35 g (37%) of 2-amino-5-(1-hydroxyethyl)benzenesulfonamide as light-brown powder. M.p. 160–162° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[C:18]([O-])([O-])=O.[K+].[K+].IC.[H-].[Na+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][C:6]2([CH3:18])[C:14]([O:16][CH3:17])=[O:15])#[N:2]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)C1(C)CCOc2cc(F)c(C#N)cc21
Temperature: 60 °C
Yield: 33.4 %

Procedure:
Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (from Example 3, Step E; 28 mg, 0.12 mmol) was diluted with acetonitrile (1 mL) followed by the addition of K2CO3 (49 mg, 0.36 mmol) and iodomethane (0.023 mL, 0.36 mmol). The reaction was then heated at 60° C. for 1 hour, then cooled and NaH (8.6 mg, 0.36 mmol) was added. The reaction was deemed complete by LC. The reaction was loaded onto a Biotage 25 samplet and purified running a gradient 5% ethyl acetate/hexane to 100% ethyl acetate/hexane to yield the title compound (10 mg, 34% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].CC[N:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:25]C.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C2C(=CC=CC=2)CN1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([N:24]1[CH2:25][C:29]2[C:28](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]1)=[O:6]
Reactant: CCN(CC)Cc1ccccc1
Reactant: CC(C)N1CCC(Oc2ccc(C(=O)Cl)c(Cl)c2)CC1
Agent: C=Cc1ccc(C=C)cc1
Agent: Cl
Agent: c1ccc2c(c1)CNC2
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)N1CCC(Oc2ccc(C(=O)N3Cc4ccccc4C3)c(Cl)c2)CC1
Reaction time: 16 h
Yield: 72.9 %

Procedure:
A stirred mixture of 2-chloro-4-[(1-isopropyl-4-piperidinyl)oxy]benzoyl chloride hydrochloride (D33) (0.20 g) and diethylaminomethyl polystyrene (3.2 mmol/g, 1.0 g) in DCM (10 ml) at rt was treated with isoindoline (0.08 g) and stirred for 16 h. The reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (1M solution in diethyl ether) and then concentrated. The residue was crystallised from acetone to yield the title compound (E62) as a white solid (0.09 g). MS electrospray (+ion) 399/401 (MH+). 1H NMR δ (DMSO-d6): 10.90 (1H, s), 7.33-7.10 (6H, m), 6.96 (1H, m), 4.82-4.51 (3H, m), 4.39 (3H, m), 3.35 (2H, m), 3.00 (2H, m), 2.11-1.80 (4H, m), 1.17 (6H, m).
Reaction SMILES: [C@H:1]1([F:12])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.[Ag]=O>[CH2:13]([O:3][C@@H:2]1[C@@H:4]([O:5][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:6]([O:7][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:8]([CH2:10][O:11][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C@@H:1]1[F:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC[C@H]1O[C@H](F)[C@H](O)[C@@H](O)[C@H]1O
Reactant: BrCc1ccccc1
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: F[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
α-D-galactopyranosyl fluoride (2.30 g, 12.62 mmol) was dissolved in dry DMF (40 ml) and, at −20° C., benzyl bromide (12.95 g, 75.72 mmol) and silver oxide (10 g) were added. The reaction mixture was stirred at −20° C. for 5 h and then at room temperature for 24 h. The salts were then filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (350 g) with 15:1 petroleum ether/ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(Cl)Cl.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:20])[CH:26]=3)[N:15]=[C:14]([NH2:19])[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(NCCNc2cc(Cl)nc(N)n2)n1
Reactant: OB(O)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Nc1nccc(NCCNc2cc(-c3cccc(Cl)c3)nc(N)n2)n1
Temperature: 100 °C

Procedure:
The product of Example 6A (69 mg, 0.246 mmol), 3-chlorophenylboronic acid (42 mg, 0.270 mmol), dichlorobis((triphenylphosphine)palladium(II) (17 mg, 0.025 mmol), and potassium carbonate (100 mg, 0.724 mmol) were combined with dioxane (5 mL) and water (1.5 mL) and heated to 100° C. overnight. The mixture was diluted with methylene chloride, washed with water, and absorbed on silica gel and purified using silica gel chromatography, eluting with a gradient of 7 N ammonia in methanol in methylene chloride (5-15%) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.98 (s, 1H) 7.76-7.86 (m, 1H) 7.61 (d, J=5.76 Hz, 1H) 7.41-7.52 (m, 2H) 7.00 (s, 1H) 6.86 (s, 1H) 6.28 (s, 1H) 6.08 (s, 2H) 5.85 (s, 2H) 5.69-5.77 (m, 1H) 3.33-3.50 (m, 4H); MS (ESI+) m/z 356.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([OH:5])[C:3]#[N:4].[CH3:7][C:8](O)([CH2:10][CH:11]([OH:13])[CH3:12])[CH3:9]>OS(O)(=O)=O>[OH:5][C:2]([C:3]1[O:13][CH:11]([CH3:12])[CH2:10][C:8]([CH3:9])([CH3:7])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CC(C)(O)C#N
Reactant: CC(O)CC(C)(C)O
Agent: O=S(=O)(O)O
Product: CC1CC(C)(C)N=C(C(C)(C)O)O1
Reaction time: 1 h
Yield: 26 %

Procedure:
To a 250 ml 3-necked flask with a thermometer, a mechanical stirrer, and a 100 ml addition funnel attached was added 200 ml of concentrated H2SO4. The acid was cooled to 0°-5° C. with a dry-ice/acetone bath while 51 g (0.6 mole) of the acetone cyanohydrin was added at such a rate so as to maintain the temperature in the -10° to 10° C. range (Note--caution must be exercised in the initial stages of the addition since a vigorous exotherm occurs). After the addition of the nitrile, 59.0 g (0.5 moles) of 2-methyl-2,4-pentanediol was added again at a rate that kept the temperature in the -10° to 10° range (see the previous note). The mixture was stirred for an additional one hour then poured onto crushed ice (~5° C.). The acidic aqueous solution was then extracted twice with ether and the ether layers discarded. The acidic aqueous layer was then poured into a large beaker which contained ~400 g of NaHCO3 and ether. The beaker was cooled with an ice-water bath and was not allowed to rise pass 36° (basification with aqueous KOH resulted in more extensive decomposition due to the higher temperature attained). The ether layer was dried over K2CO3 and concentrated. The residue obtained was distilled at 43° C. (0.5 mm) to yield 24 g (0.13 mole, 26%) of product. The structure of this alcohol was confirmed by I.R. and N.M.R.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:20][NH:21][C:22](=[O:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>N1C=CC=CC=1.O>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:26]1[CH2:27][CH2:28][CH:23]([C:22]([NH:21][CH3:20])=[O:29])[CH2:24][CH2:25]1
Reactant: CNC(=O)C1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3cc(Cl)ccc3n2)cc1
Solvent: c1ccncc1
Solvent: O
Product: CNC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccc(Cl)cc23)CC1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4,6-dichloro-2-(4-fluorophenyl)quinoline, prepared as in Example 20, and N-methylisonipecotamide as starting materials. It was obtained as off-white needles, mp 260°-265° dec on recrystallization from pyridine/water.
Reaction SMILES: N=[C:2]=[NH:3].Cl.Cl.[NH2:6][CH:7]([CH:15]([OH:43])[CH:16]([NH:24][C:25](=[O:42])[C@H:26]([CH:39]([CH3:41])[CH3:40])[NH:27][S:28](=[O:38])(=[O:37])[NH:29][N:30]1[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH3:36][N:33]1[CH2:32][CH2:31][N:30]([NH:29][S:28]([NH:27][C@H:26]([C:25]([NH:24][CH:16]([CH:15]([OH:43])[CH:7]([NH:6][C:25](=[O:42])[C@H:26]([CH:39]([CH3:40])[CH3:41])[NH:27][S:28](=[O:37])(=[O:38])[NH:29][N:30]2[CH2:31][CH2:32][N:3]([CH3:2])[CH2:34][CH2:35]2)[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:42])[CH:39]([CH3:41])[CH3:40])(=[O:37])=[O:38])[CH2:35][CH2:34]1
Reactant: N=C=N
Reactant: CC(C)[C@H](NS(=O)(=O)NN1CCN(C)CC1)C(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: Cl
Product: CC(C)[C@H](NS(=O)(=O)NN1CCN(C)CC1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NS(=O)(=O)NN1CCN(C)CC1)C(C)C

Procedure:
According to the carbodiimide coupling procedure of Example 55, the resultant compound of Example 137B was coupled to the resultant compound of Example 138 to give the desired compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]2[CH2:9][CH2:10][O:11][C:12]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:13]=3[C:14]=2[N:15]=1)=[O:5])C.[Li+].[OH-].C1COCC1>O>[Br:20][C:17]1[CH:18]=[CH:19][C:12]2[O:11][CH2:10][CH2:9][C:8]3[S:7][C:6]([C:4]([OH:5])=[O:3])=[N:15][C:14]=3[C:13]=2[CH:16]=1
Reactant: CCOC(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester (2.52 g, 7.11 mmol) and LiOH (1.53 g, 36.6 mmol) was added THF (6.5 mL) and water (6.5 mL) and allowed to stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure to remove the THF. The reaction mixture was diluted with EtOAc and 1 N HCl and warmed in a water bath to solubilize the solid. The layers were separated and the organic extract was washed sequentially with water and brine. The combined organic extracts were dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid. LC/MS (ESI+): m/z 327 (M+H)
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)=O.CO.Cl>O1CCCC1>[CH3:1][NH:2][CH2:3][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([NH:16][CH2:17][CH:18]([OH:28])[C:19]2[N:20]=[C:21]([C:24]([F:25])([F:27])[F:26])[S:22][CH:23]=2)[CH3:15])=[CH:11][CH:12]=1
Reactant: CNC(=O)COc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNCCOc1ccc(CC(C)NCC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 25 °C

Procedure:
1.2 ml of borane/dimethyl sulfide complex are added to a solution of 0.38 g of N-[2-(4-methylaminocarbonylmethoxyphenyl)-1-methylethyl]-2-hydroxy-2-(2-trifluoromethyl-thiazol-4yl)ethanamine in 20 ml of absolute tetrahydrofuran, and the mixture is heated to reflux for three hours. The 4 ml of methanol are cautiously added dropwise to the reaction mixture, and the mixture is heated to reflux for one hour. After cooling to room temperature, ethereal hydrochloric acid is added. The resulting solution is evaporated, the resulting residue is taken up in 15 ml of water, and the solution is made alkaline with concentrated ammonia and extracted several times with methylene chloride. The combined extracts are dried with sodium sulphate, evaporated and purified on a silica gel column using methylene chloride/methanol=8:2 as eluant.
Reaction SMILES: B(O)(O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:33][CH2:34]O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:24]1([N:16]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]3[C:14]([C:2]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:3]=3[CH:4]=[CH:5][NH:6]4)=[N:15]2)[CH2:26][CH2:34][CH2:33][CH2:25]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: CCO
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1cccc3[nH]ccc13)nn2C1CCCC1
Temperature: 80 °C
Yield: 95 %

Procedure:
A solution of 1H-indol-4-yl-4-boronic acid (30 mg, 0.19 mmol) in EtOH (1.65 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 0.076 mmol) in DME (6 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (0.95 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA92 (23 mg, 95% yield). ESI-MS (M+H)+ m/z calcd 319.2, found 319.1.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccnc1Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1 eq.) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) was added TBSCl (19.2 g, 150.7 mmol, 1.2 eq.) at rt. The mixture was stirred at rt for 1 h and diluted with a mixture of water (100 mL) and EtOAc (300 mL). The organic layer was washed with NH4Cl(sat.) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) as a colorless oil. LRMS (M+H+) m/z 302.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20](O)=[O:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:24][C:25]([C:27]1[S:28][C:29]([S:32](=[O:35])(=[O:34])[NH2:33])=[CH:30][CH:31]=1)=[NH:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]4[O:21][N:26]=[C:25]([C:27]5[S:28][C:29]([S:32]([NH2:33])(=[O:35])=[O:34])=[CH:30][CH:31]=5)[N:24]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C5CC5)cc(-c5ccc(Cl)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) (157 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (ethyl acetate/dichloromethane) as a light brown solid (130 mg, 52%). MS (EI) 498.1 [(M)+]; mp 294° C.
Reaction SMILES: Cl.[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:11][CH:12]=2)[CH2:4][CH2:3]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]2[CH:28]=[N:29][N:30]([CH2:32][C@H:33]3[O:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]3)[CH:31]=2)[N:21]=1.C(N(C(C)C)CC)(C)C>>[CH:2]1([C:5]#[C:6][C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([NH:26][C:27]5[CH:28]=[N:29][N:30]([CH2:32][C@H:33]6[O:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]6)[CH:31]=5)[N:21]=4)[CH2:17][CH2:18]3)=[N:11][CH:12]=2)[CH2:4][CH2:3]1
Reactant: C(#CC1CC1)c1cnc(N2CCNCC2)nc1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(N4CCN(c5ncc(C#CC6CC6)cn5)CC4)n3)cn2)C1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 5-(cyclopropylethynyl)-2-(piperazin-1-yl)pyrimidine HCl salt (172 mg, 0.44 mmol) and (s)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate was added diisopropylethylamine (169 mg, 1.311 mmol), and the reaction mixture was stirred at room temperature. LCMS showed the reaction was completed. The mixture was concentrated, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=1:2, to afford (S)-tert-butyl 2-((4-(4-(4-(5-(cyclopropylethynyl)pyrimidin-2-yl)piperazin-1-yl)-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (240 mg, 94%) as a yellowish solid. MS (ES+): C29H37N11O3 requires: 587, found: 588 [M+H]+.