Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([I:11])=[C:4]2[NH:10][N:9]=[CH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21]>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]2=[CH:8][N:9]([CH2:19][C:20]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:21])[N:10]=[C:4]2[C:3]=1[I:11]
Reactant: CC(C)(C)OC(=O)NC(=O)CCl
Reactant: Fc1cnc2cn[nH]c2c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(=O)Cn1cc2ncc(F)c(I)c2n1
Temperature: 110 °C

Procedure:
To a solution of 6-fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridine (150 mg, 0.570 mmol) in DMF (4 mL) was added Cs2CO3 (279 mg, 0.855 mmol) and tert-butyl 2-chloroacetylcarbamate (121 mg, 0.627 mmol). The mixture was heated at 110° C. for 2 hours. The mixture was then cooled and the reaction was concentrated under vacuum to give a residue. The residue was partitioned between saturated sodium bicarbonate solution and EtOAc (25 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were, dried over Na2SO4 and evaporated to give tert-butyl 2-(6-fluoro-7-iodo-2H-pyrazolo[4,3-b]pyridin-2-yl)acetylcarbamate. MS [M+H] found 421.2.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>C(Cl)(Cl)Cl>[CH2:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[CH2:14]([O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:27][CH:28]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)cc2)cc1
Agent: C=CCOc1ccc(C(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
15.0 g of PPE, 2.65 g (15.2 mmol) of the compound (12) and 4.50 g (13.4 mmol) of 4-octyloxy-4'-hydroxybiphenyl were dissolved in 120 ml of chloroform under an argon gas atmosphere and the whole was stirred at room temperature overnight. After addition of water to the reaction mixture, the whole was extracted with methylene chloride. After removal of the solvent by distillation, the residue was purified by silica gel column chromatography to obtain 5.30 g of 4- (4'-octyloxybiphenyl p-allyloxybenzoate (25) as a white solid (yield: 86.2%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:19][N:20]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](Cl)=[O:22]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:21](=[O:22])[N:20]([CH3:19])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was purified by preparative HPLC (36%, white crystals). HPLC-MS m/z=389.1 (M+1), Rt: 5.13 min.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([N:29]6[CH2:34][CH2:33][O:32][CH2:31][CH2:30]6)=[O:27])=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: O=C(c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1)N1CCOCC1
Yield: 63 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and morpholine following a procedure analogous to that described in Example 1. Yield: 63% of theory; LC (method 1): tR=2.05 min; Mass spectrum (ESI+): m/z=445 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:36][CH3:37])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH2:36][CH3:37])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:22]1)=[O:11]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.7 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-tert-butoxycarbonylaminobutyrylamino)-5-fluorophenylamino]piperidin-1-yl}ethyl ester (0.732 g, 1.4 mmol) in DCM (25 mL) was added TFA (6 mL) and the mixture stirred at RT for 1.5 h. Toluene was added and volatiles removed in vacuo, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a brown gum (0.59 g, 100%). LCMS (Method B): RT 1.76 min [M+H]+ 423.
Reaction SMILES: C(N1CCCC1C[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][C:12]=1Cl)C.[CH3:20][O-:21].[Na+].[Na]>CO>[CH3:20][O:21][C:12]1[N:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:10]([NH2:9])=[O:19]
Reactant: CCN1CCCC1CNC(=O)c1ccc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc(Cl)ccc1C(N)=O
Reaction time: 1 h

Procedure:
10.5 g (0.33 mole) of N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2,6-dichloronicotinamide are dissolved in 50 ml of absolute methanol and to this solution is added dropwise a sodium methoxide solution prepared from 0.75 g (0.33 mole) of sodium and 100 ml of absolute methanol in the course of 90 minutes at 40°-45° C. The reaction mixture is kept for 1 hour at 40°-45° C and the methanol is thereafter evaporated in vacuo to a volume of 50 ml. The concentrate is poured onto ice-water, saturated with potassium carbonate and extracted twice with benzene. The organic phases are dried over magnesium sulphate and the solvent is then evaporated in vacuo. The oily residue is chromatographed through a column of basic silica gel with benzene to which 0.5% of methanol is added. Pure N-[1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxy-6-chloronicotinamide is obtained as an oil.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[S:17]1C=[CH:20][CH:19]=[C:18]1[Mg]Br.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Br[Mg]c1cccs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1cccs1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (2.24 g, 10 mmol) in absolute THF (10 ml) was added dropwise to a 1 M solution of thiophen-2-yl-magnesium bromide in THF (20 ml, 20 mmol) under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (10 ml) and water (10 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×10 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Br:11][C:12]1[C:16]2=[C:17]3[C:22](=[CH:23][CH:24]=[C:15]2[S:14][C:13]=1[C:25](OCC)=[O:26])[N:21]=[CH:20][CH:19]=[CH:18]3.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:11][C:12]1[C:16]2=[C:17]3[C:22](=[CH:23][CH:24]=[C:15]2[S:14][C:13]=1[CH2:25][OH:26])[N:21]=[CH:20][CH:19]=[CH:18]3
Reactant: CCOC(=O)c1sc2ccc3ncccc3c2c1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: OCc1sc2ccc3ncccc3c2c1Br
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Under nitrogen atmosphere at −10° C., a solution of diisobutylaluminium hydride 1M in toluene (2.34 mL, 2.34 mmol) was added slowly to a solution of ethyl 1-bromothieno[3,2-f]quinoline-2-carboxylate (16d) in toluene (17 mL). Then the mixture was stirred at room temperature for 20 minutes more. The mixture was cooled in an ice bath and a solution of sulfuric acid 5% (5 mL) was added. The mixture was basified with saturated aqueous sodium hydrogencarbonate and extracted twice with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate and evaporated under reduced pressure to give the desired alcohol (16e) as a yellow powder (200 mg, 0.68 mmol, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CC(O)=O.CC(O)C.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1cc(C2CCNCC2)ccc1N
Reaction time: 72 h
Yield: 12 %

Procedure:
To 4-[3-(methyloxy)-4-nitrophenyl]pyridine (Example 137, step A) (4.6 g, 20 mmol) in HOAc (20 mL) is added platinum oxide (460 mg, 2 mmol). The reaction was evacuated then refilled with 60 psi H2 gas. The reaction was stirred under a H2 atmosphere for 3 days. The reaction was evacuated and the atmosphere replaced with N2. The solvent was removed under vacuum, and the residue taken up in DCM/MeOH. Silica was added, and the solvent removed under vacuum. Silica gel chromatography provided material which contained product and other impurities. This material was dissolved in iPrOH and allowed to stand overnight. The crystals which formed were collected by decanting off the solvent and rinsing with iPrOH. Obtained the title compound of step A (500 mg, 2.4 mmol, 12%) slightly wet with iPrOH as colorless crystals. 1H NMR (400 MHz, DMSO-d6) δ 6.68-6.60 (m, 3H), 3.83 (s, 3H), 3.71 (br s, 2H), 3.38-3.31 (m, 2H), 2.85-2.75 (m, 2H), 2.59-2.49 (m, 1H), 1.91-1.75 (m, 5H).
Reaction SMILES: [C:1]1(=[C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:8]#[N:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]2([C:8]#[N:9])[C:1]3([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[O:26]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C(C#N)=C2CCCCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C2(C#N)OC23CCCCC3)cc1
Temperature: 25 °C

Procedure:
2.0 g of the product from Stage 1 was refluxed for 8 hours with 2.0 g of m-chloro-perbenzoic acid, in dichloromethane. The reaction mixture was cooled to room temperature and filtered to remove precipitated m-chloro-perbenzoic acid. The filtrate was washed with saturated sodium bicarbonate solution, and the dichloromethane layer was then dried over sodium sulphate. The solvent was distilled under reduced pressure, and the residue purified by column chloromatography using a hexane:benzene (8:2) mixture as the mobile phase.
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:22])[C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[NH:12][C:13](=[O:17])[C:14]=1[O:15]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[CH2:1]([C:8]1[C:9](=[O:22])[C:10]2[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=2[NH:12][C:13](=[O:17])[C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Cc2ccccc2)c(=O)c2ccccc2[nH]c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1[nH]c2ccccc2c(=O)c(Cc2ccccc2)c1O
Temperature: 0 °C
Yield: 78.4 %

Procedure:
To a solution of 4-benzyl-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.45 g) in dichloromethane was added boron tri-bromide (4.6 mL). Upon completion of the reaction, the mixture was added to ice water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The resulting solid was recrystallized from toluene to give the title compound (0.336 g); mp 199°-200° C.; NMR: 3.97 (s,2); MS(EI): m/z=279(M). Analysis for C17H13NO3.0.1 H2O: Calculated: C, 72.64; H, 4.73; N, 4.98; Found: C, 72.65; H, 4.59; N, 4.94.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.Cl.[CH3:21][NH:22][C:23]1[S:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=1>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:26]3[N:27]=[C:23]([NH:22][CH3:21])[S:24][CH:25]=3)=[O:29])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Reactant: CNc1nc(C(=O)O)cs1
Agent: Cl
Product: CNc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3C)n2)cs1
Yield: 4.86 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(methylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (300 mg, 1.092 mmol) and 2-(methylamino)thiazole-4-carboxylic acid hydrochloride (314 mg, 1.613 mmol). The product was purified twice by Flash-chromatography (normal phase and reverse phase). Yield 4.86%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 2.56 (s, 3H), 2.93 (d, 3H), 4.28-4.43 (m, 2H), 4.47-4.61 (m, 1H), 5.04-5.12 (m, 1H), 6.43 (d, 1H), 7.31 (d, 1H), 7.49-7.56 (m, 3H), 7.67 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>ClCCl>[C:34]([O:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:14]([CH3:16])[CH3:15])/[C:10](=[C:17](\[C:19]3[CH:23]=[C:22]([CH3:24])[O:21][C:20]=3[CH3:25])/[CH3:18])/[C:9]2=[O:26])=[CH:4][CH:3]=1)(=[O:37])[CH:35]=[CH2:36]
Reactant: C=CC(=O)Cl
Reactant: CC(C)=C1C(=O)N(c2ccc(O)cc2)C(=O)/C1=C(\C)c1cc(C)oc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(N2C(=O)C(=C(C)C)/C(=C(/C)c3cc(C)oc3C)C2=O)cc1
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution obtained by dissolving 211 mg of N-(4-hydroxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide obtained in Example 5 in 5 ml of dichloromethane, 72 mg of triethylamine was added, followed by dropwise addition of 66 mg of acryloyl chloride in 10 minutes. The reaction was carried out at room temperature for 30 minutes with stirring. After the reaction, the reaction solution was well washed with water, dried over anhydrous magnesium sulfate, and subjected to removal of the solvent by distillation. The resulting residue was purified by column chromatography (filler: Wakogel C-300, eluent: a mixed solvent of n-hexane and ethyl acetate) to give pale red crystals of N-(4-acryloyloxyphenyl)-2-[(E)-1-(2,5-dimethyl-3-furyl)ethylidene]-3-isopropylidenesuccinimide in yield of 44.0%.
Reaction SMILES: C(#N)C.Br.[CH2:5]([O:7][C:8]([CH:10]1[CH2:19][CH2:18][C:13]2[N:14]=[C:15]([NH2:17])[S:16][C:12]=2[CH2:11]1)=[O:9])[CH3:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(N(CC)CC)C>[CH2:5]([O:7][C:8]([CH:10]1[CH2:19][CH2:18][C:13]2[N:14]=[C:15]([NH:17][C:20](=[O:22])[CH3:21])[S:16][C:12]=2[CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)C1CCc2nc(N)sc2C1
Reactant: CC(=O)OC(C)=O
Agent: Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCc2nc(NC(C)=O)sc2C1
Yield: 120.1 %

Procedure:
A 500 ml reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 280 ml of acetonitrile, 71 g of 2-amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester [(III), R1=ethyl] and 38.75 g of acetic anhydride. 38.03 g of triethylamine were dropwise added to the resulting suspension in about 10 minutes. The suspension was refluxed, obtaining complete dissolution at a temperature ranging from 70 to 75° C. After approx. 2 hours 30 minutes the solution was concentrated to dryness, and the residue was crystallized from 450 ml of isopropanol to obtain 74.5 g of 2-acetylamino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])(=[O:16])=[O:15])[S:11][CH:12]=1)(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>C(O)C>[N:25]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[CH3:24])(=[O:16])=[O:15])[S:11][CH:12]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Agent: [Na+]
Solvent: CCO
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCN=[N+]=[N-])cs1
Yield: 72.8 %

Procedure:
A mixture of EXAMPLE 191A (1.00 g, 2.43 mmol) and sodium azide (791 mg, 12.17 mmol) in ethanol (30 mL) was refluxed for 2.5 h. The solvent was evaporated and the crude material was extracted with ethyl acetate. The organic phase was dried (Sodium sulfate) and the solvent was evaporated. The crude product was purified by flash column chromatography on silica gel eluting with 2-5% acetone in DCM to yield the title product (633 mg, 1.77 mmol, 70%): MS (Ionspray, [M+H]+) m/z 357.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:21][CH3:22])([O:19][CH3:20])=[O:18])[CH2:10][C:11]([OH:13])=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]1(C)C=CC(S(OC)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.C(OCC)(=O)C>[Si:1]([O:8][C@H:9]([CH2:14][C:15](=[O:23])[CH2:16][P:17]([O:19][CH3:20])([O:21][CH3:22])=[O:18])[CH2:10][C:11]([O:13][CH3:24])=[O:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COP(=O)(CC(=O)C[C@H](CC(=O)O)O[Si](C)(C)C(C)(C)C)OC
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)C[C@@H](CC(=O)CP(=O)(OC)OC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.4 %

Procedure:
2.58 g (7.0 mmol.) of (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoic acid was dissolved in 16 ml of acetone. To the acetone solution were added 6.52 g (35 mmol.) of methyl p-toluenesulfonate and 1.06 g (7.7 mmol.) of potassium carbonate, and the resulting mixture was vigorously stirred for 6 hours at room temperature to give a reaction solution. The reaction solution was mixed with 16 ml of water and then extracted with 20 ml of toluene. The toluene portion was dried over anhydrous magnesium sulfate and concentrated to give an oil. The oil was treated by column chromatography (eluent: ethyl acetate) to give 1.91 g (5.0 mmol.) of methyl (R)-3-t-butyldimethylsilyloxy-6-dimethoxyphosphinyl-5-oxohexanoate as an oil (yield: 71%).
Reaction SMILES: NC(N)CCCCCC(OC[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26].C(=O)C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCCCCCN
Reactant: NC(N)CCCCCC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O=Cc1ccccc1
Product: NCCCCCCNc1ccccc1
Yield: 100 %

Procedure:
To prepare 1-amino-6-phenylmethoxycarbonyl-amino-hexane (23), an equimolar mixture (0.01 mol) of 1,6-diaminohexane and benzaldehyde in 25 mL of methylene chloride was stirred for 5 hr in the presence of 1.5 g of anhydrous magnesium sulfate at room temperature. After removing the drying agent by filtration the filtrate was evaporated to dryness under reduced pressure to give 2 g (100% yield) of crude 1-amino-6-phenylamino-hexane 22 as a colorless oil; NMR(CDCl3) 1.1-1.9(m, 10H, hexane CH2 -2,-3,4,-5, NH2); 2.6(m, 2H, CH2 -1); 3.51(m, 2H, hexane CH2 -6); 7.1-7.8 (m, 5H, aromatic); 8.16(s, 1H, imine CH). To a mixture of 2 g (0.01 mol) of 22 and 1.4 mL (0.01 mol) of triethylamine in 20 mL of methylene chloride. Then 1.78 g (0.01 mol) of benzylchloroformate was added dropwise at -5° C. The resulting mixture was stirred for 0.5 hr at 0° C. and for 2 hr at room temperature then diluted to 50 mL with methylene chloride and washed with water (20 ml), 2% sodium bicarbonate (20 ml), water and saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of solvent under reduced pressure the residue was dissolved in 5 mL of ethanol and 10 mL of 2N hydrochloric acid was added. The resulting mixture was stirred for 6 hr at room temperature then evaporated to dryness under reduced pressure. The residue was diluted to 50 mL with water and washed with ethyl ether (2 × 15 ml). The water phase was evaporated under reduced pressure and the product 23 was purified by crystallization from a small portion of water with a yield of 42%; mp 175°-178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:45])=[C:21]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:57]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:33]=[CH:32][C:31]3[N:30]4[CH2:34][CH:35]([N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[CH3:57])[CH2:36][C:29]4=[CH:28][C:27]=3[CH:26]=2)[C:22]([CH3:45])=[C:21]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc3c(c2)cc2n3CC(NC(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccc3c(c2)cc2n3CC(N(C)C(=O)OC(C)(C)C)C2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The product from Example 412, Step 3 (130 mg, 0.18 mmol) was dissolved in DMF (1 mL). Sodium hydride (60% dispersion in mineral oil, 15 mg, 0.36 mmol) was added to the mixture. After 10 min of vigorous stirring at room temperature, iodomethane (35 μL, 0.54 mmol) was added to the mixture. The mixture was stirred an additional 10 min at room temperature, and then was quenched with the addition of aqueous saturated NH4Cl solution (5 mL). The mixture was extracted with CH2Cl2 (5 mL). The organic extracts were concentrated. The residue was 97% pure by UPLC analysis and used without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[C:15]([NH2:21])=[N:16][CH:17]=[C:18](Br)[CH:19]=2)=[O:13])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].[N:22]1([CH2:28][C:29]2[S:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([NH:11][C:12](=[O:13])[C:14]2[CH:19]=[C:18]([C:32]3[S:33][C:29]([CH2:28][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:30][CH:31]=3)[CH:17]=[N:16][C:15]=2[NH2:21])[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(NC(=O)c2cc(Br)cnc2N)ccn1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Product: CC(=O)Nc1cc(NC(=O)c2cc(-c3ccc(CN4CCOCC4)s3)cnc2N)ccn1

Procedure:
Reaction of N-(2-acetamido-4-pyridyl)-2-amino-5-bromo-pyridine-3-carboxamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A36”; HPLC/MS: 1.14 min, [M+H]=453;