Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[S:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[K+]>C1COCC1>[CH3:22][O:21][C:15]1[CH:14]=[C:13]([NH:12][C:8]2[S:9][C:10]([CH3:11])=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:18]=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: CCOC(=O)c1nc(Nc2ccc(OC)c(OC)c2)sc1C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(C(=O)O)c(C)s2)cc1OC
Temperature: 50 °C
Yield: 57.8 %

Procedure:
A mixture of 4.1 g (12.7 mmol) 2-(3,4-Dimethoxy-phenylamino)-5-methyl-thiazole-4-carboxylic acid ethyl ester and 7.6 ml 5M aq. KOH in 50 ml THF was heated to 50° C. for 16 h. After evaporation of the volatiles 100 ml water and 6 ml HOAc was added and the mixture was extracted 3× with 500 ml ethyl acetate. The combined organic layers were washed 3× with 200 ml water and concentrated at 40° C. under reduced pressure until precipitation started. After cooling to room temperature the crystals were filtered off, washed 3× with 10 ml ethyl acetate and dried to yield 2.16 g (44.5%) of the title compound. MS (m/e): 295.3 (MH+, 100%)
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([CH:11]=[O:12])=[C:8]([CH3:13])[CH:7]=[C:6]([CH3:14])[C:5]=2[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.[CH3:25][Si:26]([CH3:46])([CH3:45])[CH2:27][CH2:28][O:29][CH2:30][N:31]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[N:32]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C(Cl)Cl.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>[CH3:13][C:8]1[CH:7]=[C:6]([CH3:14])[C:5]2[N:4]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=3)(=[O:17])=[O:16])[CH:3]=[C:2]([C:35]3[N:31]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:46])([CH3:45])[CH3:25])[N:32]=[CH:33][CH:34]=3)[C:10]=2[C:9]=1[CH:11]=[O:12]
Reactant: CC1(C)OB(c2ccnn2COCC[Si](C)(C)C)OC1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(Br)c3c(C=O)c(C)cc(C)c32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccnn3COCC[Si](C)(C)C)c3c(C=O)c(C)cc(C)c32)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-bromo-5,7-dimethyl-1-tosyl-1H-indole-4-carbaldehyde (100 mg, 0.246 mmol), 1-(2-trimethylsilylethoxy)methyl-1H-pyrazole-5-boronic acid pinacol ester (CAS #: 903550-12-9) (239 mg, 0.738 mmol), and K3PO4 (157 mg, 0.738 mmol) in DME (1 mL)/H2O (0.5 mL) was added Pd(PPh3)4 (56.9 mg, 0.049 mmol), and then the mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled down to room temperature. The mixture was diluted with CH2Cl2. The bi-phase layer was partitioned. The organic layer was separated, dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel flash column chromatography [heptane/(30% EtOAc in CH2Cl2)=1/0 to 4/6] to give the title compound. MS (ESI+) m/z 524.2 (M+H).
Reaction SMILES: [N:1]1(CC(N)=O)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[N:4][CH:3]=[CH:2]1.B>>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[N:4][CH:3]=[CH:2]1
Reactant: NC(=O)CN1C=CN=Cc2ccccc21
Agent: B
Product: C1=CNc2ccccc2C=N1

Procedure:
In the manner given in Example 1, N,N-dimethyl-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4benzodiazepine-1-acetamide is reduced with borane to give 1-[2-(dimethylamino)ethyl]-8-chloro-5,6-dihydro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4-benzodiazepine.
Reaction SMILES: [C:1]([O-])(=O)C.[Na+].C=O.C([BH3-])#N.[Na+].[OH:12][CH2:13][CH:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.C([O-])(O)=O.[Na+]>CO>[OH:12][CH2:13][CH:14]1[N:19]([CH3:1])[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNC(CO)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CCN(C(=O)OC(C)(C)C)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
0.303 g of sodium acetate, 0.375 g of formaldehyde and 0.218 g of sodium cyanoborohydride are added to a solution of 0.5 g of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate in 50 ml of MeOH and stirred for 1 hour at RT. A saturated solution of NaHCO3 is added, it is extracted with DCM, the organic phase is dried over Na2SO4 and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, eluting with DCM/MeOH mixture. 0.31 g of the expected compound is obtained.
Reaction SMILES: [CH2:1]([C@:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([CH2:9][CH2:10][CH2:11][CH2:12][B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)[C:5]([O:7][CH3:8])=[O:6])[CH:2]=C.[O:30]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:26]([O:25][C:23]([NH:22][C@@:4]([CH2:1][CH:2]=[O:30])([CH2:9][CH2:10][CH2:11][CH2:12][B:13]1[O:14][C:15]([CH3:20])([CH3:21])[C:16]([CH3:18])([CH3:19])[O:17]1)[C:5]([O:7][CH3:8])=[O:6])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=[O+][O-]
Reactant: C=CC[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@](CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 67 %

Procedure:
A solution of (R)-methyl 2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (1.90 g, 4.62 mmol) in dichloromethane (90 mL, 0.05 M) was cooled to −78° C. and treated with ozone until a pale blue-gray color appeared. After TLC indicated the absence of starting material, the ozone inlet tube was replaced with nitrogen and nitrogen was bubbled through the solution for 20 min to remove any excess ozone. Triphenylphosphine (3.6 g, 13.8 mmol, 3 equiv) was added in one portion, the cooling bath was removed and the mixture was stirred for 4 h. The solution was concentrated and purified by MPLC (1-50% ethyl acetate in heptane over 6 CV) gave (R)-methyl 2-(tert-butoxycarbonylamino)-2-(2-oxoethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (1.28 g, 67%). Rf 0.55 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 9.66 (s, 1H), 5.62 (br s, 1H), 3.75 (s, 3H), 3.60 (br d, J=17.4 Hz, 1H), 2.95 (d, J=17.4 Hz, 1H), 2.30-2.15 (m, 1H), 1.70-1.54 (m, 1H), 1.40 (s, 9H), 1.39-1.24 (m, 4H), 0.74 (t, J=7.8 Hz, 2H); ESI-LCMS m/z calcd for C20H36BNO7: expected 413.3. found 414.3 (M+H)+.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]C.C(OC(=O)C)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCCCCCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCCC(=O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCCCCCCCCC
Product: C=CCCCCCCC
Temperature: 255 °C

Procedure:
A mixture of decanoic acid (100 g, 0.581 mol), acetic anhydride, dichlorobis(triphenylphosphine)palladium (0.0407 g, 5.81×10-5 mol), and triphenylphosphine (0.761 g, 0.00290 mol) was heated under a slow stream of nitrogen using an oil bath maintained at 255° C. As product distilled from the reactor, it was continuously replaced with a mixture of decanoic acid and acetic anhydride, identical in ratio to that of the initial charge, in a rate that maintained the initial level of the reactor contents throughout the course of the entire reaction. The distillate products from several runs which contained varied decanoic acid: acetic anhydride ratios were examined by GC analysis (using n-decane as internal standard) and the catalyst efficiency and product α-olefin selectivity calculated. For example, using of a 1:1.5 ratio of decanoic acid:acetic anhydride throughout the course of an entire reaction produced 1-nonene with a catalyst TON of 14,800 and an α-olefin selectivity of 97.4%. The data for this series of reactions appears in Table 4.
Reaction SMILES: [CH2:1]1[C@H:7]2[NH:8][C@H:3]([CH2:4][CH:5]([OH:9])[CH2:6]2)[CH2:2]1.Br[CH2:11][CH2:12][CH2:13][F:14].C(N(CC)CC)C>CN(C=O)C>[F:14][CH2:13][CH2:12][CH2:11][N:8]1[CH:7]2[CH2:1][CH2:2][CH:3]1[CH2:4][CH:5]([OH:9])[CH2:6]2
Reactant: FCCCBr
Reactant: OC1C[C@H]2CC[C@@H](C1)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CC2CCC(C1)N2CCCF
Temperature: 60 °C
Reaction time: 10 h

Procedure:
A mixture of nortropine (381.6 mg), 1-bromo-3-fluoropropane (634.4 mg) and triethylamine (0.42 ml) in DMF (7.5 ml) was heated to 60° C. and stirred at this temperature for 10 h. The solvent was then removed in vacuo. The product with the molecular weight of 187.26 (C10H18FNO) was obtained in this way; MS (ESI): 188 (M+H+).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:36]2[CH2:45][CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[C:41]([O:46][Si](C(C)(C)C)(C)C)[CH:42]=3)[CH2:37]2)=[C:13]([N:15]([CH2:33][CH2:34][F:35])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:19]([F:32])[CH:18]=2)[CH:14]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.CO.N>O1CCCC1>[F:35][CH2:34][CH2:33][N:15]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:19]([F:32])[CH:18]=1)[C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[CH:11][C:12]=1[CH:36]1[CH2:45][CH2:44][C:43]2[CH:42]=[C:41]([OH:46])[CH:40]=[CH:39][C:38]=2[CH2:37]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CCC(c1ccc(O[Si](C)(C)C(C)(C)C)cc1N(CCF)Cc1ccc(OCCN3CCCCC3)c(F)c1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: Oc1ccc2c(c1)CCC(c1ccc(O)cc1N(CCF)Cc1ccc(OCCN3CCCCC3)c(F)c1)C2
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
solution of {5-(tert-butyldimethylsilyloxy)-2-[6-(tert-butyldimethylsilyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl]phenyl}(2-fluoroethyl)[3-fluoro-4-(2-piperidin-1-ylethoxy)benzyl]amine (200 mg) in tetrahydrofuran (10 ml) were sequentially added tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran) (1 ml) and hydrochloric acid-methanol solution (1 ml) on an ice bath, and the solution was stirred for 8 hours at 50° C. The reaction solution was alkalinized by adding aqueous ammonia, the solution was extracted with ethyl acetate, then washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate-methanol system) to provide the title compound (140 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[ClH:15].[CH3:16][OH:17]>>[ClH:15].[NH:2]=[C:1]([O:17][CH3:16])[C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C#N)c(C)cc1C
Reactant: CO
Agent: Cl
Product: COC(=N)c1cc(C(=O)OC)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Into a 50-mL three neck round-bottom flask, was placed a solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 900 mg, 4.28 mmol, 1.00 equiv, 90%) in methanol (20 mL). Hydrogen chloride gas was introduced by bubbling through the solution for 0.5 hr. The reaction mixture was then transferred into a 30-mL sealed tube and stirred overnight at room temperature. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (30 mL) and extracted with water (10 mL). The aqueous was concentrated in vacuo to obtain the title compound as a white solid (200 mg, 15%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:31][C:30](=[O:32])[C:29]3[CH:33]=[C:34]([N+:37]([O-:39])=[O:38])[CH:35]=[CH:36][C:28]=3[N:27]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:27][C:28]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][C:29]=2[C:30]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:32])=[O:31])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)c1ccc(-c2nc3ccc([N+](=O)[O-])cc3c(=O)o2)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])cc2C(=O)Nc2cccc(OCc3ccccc3)c2)cc1
Yield: 42 %

Procedure:
Using the procedure described in Example 91, Part B, 3-benzyloxyaniline (2.5 mmol) and 2-(4-tert-butylphenyl)-6-nitro-4H-3,1-benzoxazin-4-one (2.8 mmol) yielded 550 mg (42%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:24]3[CH2:23][CH2:22][N:21]([C:15]4[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=4[Cl:13])[CH2:26][CH2:25]3)[N:10]=2)[CH:7]=1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: ClCc1cn2cc(Br)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1ccc(N2CCN(Cc3cn4cc(Br)ccc4n3)CC2)c(Cl)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 6-bromo-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 15, Step 1; 0.582 g), 1-(2,4-dichlorophenyl)piperazine (Example 31, Step 1; 0.548), triethylamine (Aldrich; 0.288 g), and THF (5 mL) is stirred at 80° C. for 6 h, at which time it is cooled and then partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate and concentrated. Chromatography of the residue on silica gel using methanol/dichloromethane (2/98) and crystallization gives 0.710 g of the title compound; mp 137-138° C.; MS m/z 438, 440; IR (mineral oil) 1479, 1341, 1058, 2810, 803 cm-1. 1H NMR (CDCl3) δ2.78, 3.09, 3.80, 6.96, 7.16-7.23, 7.35, 7.48, 7.55, 8.24.
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[N-]=C=S>CCCCC>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Reactant: NC1CCCCC1
Agent: [N-]=C=S
Solvent: CCCCC
Product: CC(C)(C)N=NC1(NC(=S)NC2CCCCC2)CCCCC1
Reaction time: 3 h

Procedure:
To 8.4 grams (0.0363 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 3.6 grams (0.0363 moles) of cyclohexylamine at room temperature. A solid slowly started to form and pentane was added to keep the reaction mixture from solidifying and the reaction mixture was stirred for 3 hours and the pentane stripped off to leave a yellow solid weighing 11.4 grams (95% crude yield). The product melted at 100°-102° C. and the infrared spectrum of the product had a strong broad band at 1520-1540 cm-1 and a NH band at 3220 cm-1. The isothiocyanate band at 2040 cm-1 was absent.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22](B4OC(C)(C)C(C)(C)O4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:33][S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[CH:10]=1.N#N.Br[C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][N:44]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][N:44]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:33][S:34]([CH:37]2[CH2:38][CH2:39]2)(=[O:35])=[O:36])[CH:10]=1
Reactant: CC1(C)OB(c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)OC1(C)C
Reactant: Fc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: COCCOC
Product: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4ccc(F)cn4)ccc32)c1)C1CC1
Yield: 14.1 %

Procedure:
A solution of N-(2′,4′-difluoro-5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)-[1,1′-biphenyl]-3-yl)cyclopropanesulfonamide (0.15 g, 0.272 mmol) in 1,2-dimethoxyethane (5 ml) was degassed by N2 bubbling for 5 min. 2-Bromo-5-fluoropyridine (0.057 g, 0.326 mmol, 1.2 eq.) was added and the mixture was degassed for another 5 min. Pd(dppf)Cl2 (0.011, 0.013 mmol, 0.05 eq.) and aqueous sodium carbonate (0.072, 0.680 mmol, 2.5 eq.) were added and the procedure of Example 1(d) was followed. The crude residue of the product was purified by column chromatography (60-120 silica gel, 80% ethyl acetate in hexane) to yield the title product in 14.1% yield (0.02 g). 1H NMR (400 MHz, DMSO-d6): δ 10.23 (s, 1H), 8.75 (s, 1H), 8.68-8.67 (d, 1H), 8.48 (d, 1H), 8.20-8.13 (m, 2H), 7.86-7.743 (m, 3H), 7.61-7.60 (d, 2H), 7.51-7.43 (m, 2H), 7.30-7.25 (m, 1H), 2.89-2.86 (t, 1H), 1.03-1.02 (d, 4H); LC-MS (ESI): Calculated mass: 520.53; Observed mass: 521.2 [M+H]+ (rt: 1.64 min).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15](Cl)=[O:16].[NH2:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1.O>CN(C)C=O>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([NH:18][C:19]1[S:20][C:21]([CH3:24])=[CH:22][N:23]=1)=[O:16]
Reactant: CN1C(C(=O)Cl)=C(O)c2ccccc2S1(=O)=O
Reactant: Cc1cnc(N)s1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)s1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.23 gm (4.5 millimols) of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid chloride-1,1-dioxide were dissolved in 10 ml of dimethylformamide and 1.0 gm (9 millimols) of 2-amino-5-methyl-thiazole was added in portions. The reaction mixture was stirred at room temperature for 24 hours, and then 40 ml of water were added. The mixture was stirred at room temperature for 20 minutes, and the precipitate which had formed was filtered off, washed and dried. After recrystallization from ethylene chloride 0.4 gm (25% of theory) of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:37][OH:38].C([O-])([O-])=O.[K+].[K+]>CCO>[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32](=[NH:33])[NH:37][OH:38])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:34])([CH3:3])([CH3:4])[CH3:2]
Reactant: NO
Reactant: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Yield: 54.2 %

Procedure:
{3-[5-Cyano-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester (1.5 g, 3.17 mmol), hydroxylamine hydrochloride (660 mg, 9.5 mmol) and K2CO3 (657 mg, 4.75 mmol) are dissolved in EtOH (40 ml) and heated to reflux for 12 h. The reaction mixture was cooled and the product was isolated by filtration to give 870 mg (54%) of {3-[5-(N-Hydroxycarbamimidoyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:4].[OH-].[Na+].S(=O)(=O)(O)O.[CH2:27](O)C>>[CH3:27][C:8]1[S:9][C:5]([C:3]([OH:2])=[O:4])=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[N:7]=1
Reactant: COC(=O)CCCCCCc1ncsc1C(=O)OC
Reactant: CCO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(CCCCCCC(=O)O)c(C(=O)O)s1

Procedure:
The solution of 8 g of crude 2-methyl-4-(6-carbomethoxyhexyl)-thiazole-5-carboxylic acid methylester (VIII, R1 = CH3) in 25 ml of ethanol was treated with 40 ml of 2 N sodium hydroxide solution. The reaction mixture was refluxed for 30 minutes, then acidified with 5 N sulphuric acid under ice-cooling. After extracting the aqueous reaction mixture with 3 × 75 ml of ethyl acetate, the extract was dried over sodium sulphate and evaporated in vacuo. The obtained crude product was recrystallized from a mixture of acetone and n-hexane, affording 5.3 g of 2-methyl-4-(6-carboxyhexyl)-thiazole-5-carboxylic acid (IX, R1 = CH3). M.p.: 147-149° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH:21]=4)=[O:18])[C@@H:13]([CH3:32])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4](S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH3:42][N:43](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:42]([C:2]1[C:10]2[C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:31])[NH:27][CH:28]([CH3:30])[CH3:29])[CH:21]=4)=[O:18])[C@@H:13]([CH3:32])[CH2:12]3)=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1)#[N:43]
Reactant: CC(C)NC(=O)c1cccc(NC(=O)N2CCN(c3ncnc4c3c(Br)cn4S(=O)(=O)c3ccccc3)C[C@@H]2C)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)NC(=O)c1cccc(NC(=O)N2CCN(c3ncnc4[nH]cc(C#N)c34)C[C@@H]2C)c1
Temperature: 150 °C

Procedure:
To a solution of (S)-4-(5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)-phenyl)-2-methylpiperazine-1-carboxamide from step D (70 mg, 0.11 mmol) in DMF (2 ml) was added Zn(CN)2 (26 mg, 0.22 mmol) and Pd(PPh3)4 (13 mg, 0.011 mmol). The mixture was heated at 150° C. for 3 min via microwave, cooled to room temperature, and filtered through a pad of celite. The solution was concentrated under vacuum, and the residue was treated with NaOH and MeOH for 2 hrs. The product was purified by Prep-HPLC to obtain (S)-4-(5-cyano-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)phenyl)-2-methylpiperazine-1-carboxamide as a white solid.